JP2021503447A - Quinazolinone compounds and their use - Google Patents

Abstract

The present invention relates to a series of quinazolinones compounds and their use as PI3Kα inhibitors, specifically to compounds represented by formula (I), tautomers thereof and pharmaceutically acceptable salts thereof. [Chemical 1]

Description

Detailed description of the invention

[Cross-reference of related applications]
This application claims the priority of Chinese patent application CN201711116253.5, which has a filing date of November 13, 2017.

〔Technical field〕
The present invention relates to a series of quinazolinones compounds and their use as PI3Kα inhibitors, specifically to compounds represented by formula (I), tautomers thereof and pharmaceutically acceptable salts thereof.

[Background technology]
Phosphatidylinositol-3-kinase (PI3K) is composed of a regulatory subunit p85 or p101 and a catalytic subsystem p110 (further classified into four subtypes, p110α, p110β, p110δ, and p110γ). Phosphatidylinositol 4,5-bisphosphate (PIP2) is a lipokinase that catalyzes the inositol ring 3'-OH in phosphatidylinositol 4,5-bisphosphate (PIP2) and phosphatidylinositol 3,4,5-triphosphate. It plays an important role in cell proliferation, survival and metabolism by producing (phosphatidylinositol 3,4,5 -trisphosphate, PIP3) and activating downstream Akt. In tumor cells, PI3K is overexpressed, causing rapid growth and growth of tumor cells.

The tumor suppressor gene PTEN (Phosphatase and TENsin homolog deleted on chromosome 10) dephosphorylates PIP3 to produce PIP2, causing negative feedback regulation of the PI3K signaling pathway, inhibiting cell proliferation and causing apoptosis. Facilitate. Frequent mutations and amplifications of the PI3K gene in cancer and deletion of the PTEN gene in cancer suggest that overexpression of PI3K is closely associated with tumorigenesis.

Zhang hao et al. (Bioorganic Medicinal Chemistry, 2015 (23): 7765-7776.) Found that compounds A2 and A10 (Control Examples R011 and R012) had a good inhibitory effect on PI3K.

[Outline of Invention]
The present invention provides a compound represented by the formula (I), an isomer thereof, or a pharmaceutically acceptable salt thereof.

During the ceremony
R ₁ is NH ₂ , C _1-6 alkyl, C selected from H, F, Cl, Br, I, OH, NH ₂ or CN, or optionally substituted with 1, 2 or 3 Rs. Selected from _1-6 heteroalkyl or C _3-6 cycloalkyl-O-;
R ₂ is selected from phenyl or 5- to 6-membered heteroaryl optionally substituted with 1, 2 or 3 R;
R ₂ is selected from phenyl and 5-6 membered heteroaryl, said phenyl and 5-6 membered heteroaryl being optionally substituted with 1, 2 or 3 Rs;
R ₃ , R ₄ , and R ₅ are independently selected from H, F, Cl, Br, I, OH, or NH ₂ ;
R ₆ is selected from H or optionally substituted with 1, 2 or 3 Rs C _1-6 alkyl, C _1-6 heteroalkyl, C _3-7 cycloalkyl or _3-6 member heterocycloalkyl Selected from;
R ₇ is selected from H, or from C _1-6 alkyl optionally substituted with 1, 2 or 3 R;
Alternatively, R ₆ and R ₇ together form a 3- to 7-membered ring arbitrarily substituted by 1, 2 or 3 R;
L ₁ is selected from single bonds or from -C _1-6 alkyl-arbitrarily substituted by 1, 2 or 3 R;
L ₂ is selected from single bonds or arbitrarily substituted with 1, 2 or 3 R-C _3-7 cycloalkyl-;
Each R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally substituted with 1, 2 or 3 _{R'C 1-6} alkyl or C _{1 -6} Selected from heteroalkyl;
Each R'is independently selected from F, Cl, Br, I, OH, NH ₂ , CN, Me or Et;
The 3- to 6-membered heterocycloalkyl and the 5- to 6-membered heteroaryl contain 1-4 heteroatoms independently selected from N, O or S;
The heteroatom or heteroatom group in the C _1-6 heteroalkyl is independently N, -O-, -S-, -NH-, -C (= O) NH-, -C (= O)-or- Selected from C (= O) O-; the number of heteroatoms or heteroatoms is 1, 2, 3 or 4.
In some aspects of the invention, the R is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally substituted with 1, 2 or 3 R'C ₁ Selected from _-3 alkyl or C _1-3 alkoxy, other variables are as defined in the present invention.
In some aspects of the invention, the R is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally substituted with 1, 2 or 3 R', Me, Et or

The other variables are as defined in the present invention.

In some aspects of the invention, the R is H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , Et,

The other variables are as defined in the present invention.
In some aspects of the invention, the R ₁ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally substituted with 1, 2 or 3 Rs C _{1 -3} alkyl, C _1-3 alkoxy are selected from -O- C _1-3 alkylamino or cyclopropyl, other variables are as defined in the present invention.

In some aspects of the invention, said R ₁ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally by 1, 2 or 3 R, respectively. Replaced Me, Et,

The other variables are as defined in the present invention.

In some aspects of the invention, the R ₁ is H, F, Cl, Br, I, OH, NH ₂ , CN, Me, Et, CF ₃ ,

The other variables are as defined in the present invention.

In some aspects of the invention, said R ₂ is selected from phenyl, thiazolyl, frills, oxazolyl, isoxazolyl, pyrrolyl or thienyl optionally substituted with 1, 2 or 3 Rs, with other variates of the invention. As defined in.

In some aspects of the invention, the R ₂ was optionally replaced by 1, 2 or 3 R's.

Is selected from.

In some aspects of the invention, the R ₂ is

The other variables are as defined in the present invention.

In some aspects of the invention, the R ₆ is selected from H or optionally substituted with 1, 2 or 3 Rs, C _1-3 alkyl, C _1-3 heteroalkyl, cyclopropyl, cyclobutyl. , Oxetanyl or tetrahydrofuranyl, with other variates as defined in the present invention.

In some aspects of the invention, the R ₆ is selected from H or optionally substituted with 1, 2 or 3 R Me, Et,

The other variables are as defined in the present invention.

In some aspects of the invention, the R ₆ is H, Me, Et, CF ₃ ,

The other variables are as defined in the present invention.

In some aspects of the invention, the R ₇ is selected from H, Me or Et, and the other variables are as defined in the invention.

In some aspects of the invention, the structural unit

Was arbitrarily replaced by 1, 2 or 3 Rs

The other variables are as defined in the present invention.

In some aspects of the invention, the structural unit

Is

And other variables are as defined in the present invention.
In some aspects of the present invention, wherein L ₁ is selected from a single bond, or one, two or three -CH ₂ optionally substituted by _{R -, - CH 2 -CH 2} -,

The other variables are as defined in the present invention.

In some aspects of the present invention, wherein L ₁ is a single _{bond, -CH 2 -, - CH 2} -CH 2 -,

The other variables are as defined in the present invention.

In some aspects of the invention, said L ₂ is selected from single bonds or optionally substituted with 1, 2 or 3 R's-cyclopropyl-, -cyclobutyl- or-cyclopentyl-. Other variables are as defined in the present invention.

In some aspects of the invention, the L ₂ is a single bond,

The other variables are as defined in the present invention.

In some aspects of the invention, the structural unit

Is

The other variables are as defined in the present invention.

Furthermore, some aspects of the invention are due to any combination of said variables.

In some aspects of the invention, the compound, its isomers or pharmaceutically acceptable salts thereof

Selected from
During the ceremony
n is selected from 1, 2 or 3;
m is independently selected from 1, 2 or 3;
R ₈ is independently selected from H, F, Cl, Br, I, OH, NH ₂ or independently substituted with 1, 2 or 3 Rs of C _1-3 alkyl. Or selected from C _1-3 alkoxy;
R, R ₁ , R ₃ to R ₇ are as defined in the present invention;
R ₃ , R ₄ , R ₅ , R ₆ and R ₇ are as defined in the present invention;
If R ₈ is not H, the carbon atom marked with "*" is a chiral carbon atom, either present in the form of a single enantiomer of (R) or (S), or rich in one enantiomer. Exists.

In some aspects of the present invention, the R ₈ each independently H, F, Cl, Br, I, OH, NH 2, Me, Et,

The other variables are as defined in the present invention.

In some aspects of the invention, the compound, its isomers or pharmaceutically acceptable salts thereof

And
In the equation, m, R, R ₁ , R ₃ to R ₈ are as defined in the present invention;
R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined in the present invention.

The present invention further provides compounds selected from the following, isomers thereof or pharmaceutically acceptable salts thereof:

In some aspects of the invention, the compound, its isomers or pharmaceutically acceptable salts thereof

Is selected from.

The present invention further provides a pharmaceutical composition comprising the compound as an active ingredient in an effective therapeutic amount, an isomer thereof or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

The present invention provides the use of the compound, an isomer thereof or a pharmaceutically acceptable salt thereof or the composition thereof in the production of a drug related to a PI3Kα inhibitor.

In some aspects of the invention, the PI3Kα inhibitor-related drug is a drug for the treatment of pain and pain-related disorders, and is a drug for the treatment of solid tumors.
Definitions and Descriptions Unless otherwise stated, the following terms and phrases used in the text refer to the following meanings: Certain terms and phrases should not be understood as uncertain or unclear, unless otherwise defined, but should be understood in their ordinary sense. When a product name appears in the text, it refers to the corresponding product or its active ingredient. The term "pharmaceutically acceptable" as used herein is directed to a compound, material, composition and / or dosage form and is in contact with human and animal tissues within reliable medical judgment. Applied for use, without excessive toxicity, irritation, allergic reactions or other problems or complications, with a reasonable benefit / risk ratio.

The term "pharmaceutically acceptable salt" is a salt of a compound of the present invention prepared from a compound having a specific substituent found in the present invention and a relatively non-toxic acid or base. Is. If the compounds of the invention contain relatively acidic functional groups, base addition salts may be added to a pure solution or suitable inert solvent by contacting a sufficient amount of base with the neutral form of the compound. Obtainable. Pharmaceutically acceptable base addition salts include sodium, potassium, calcium, ammonium, organic amines or magnesium salts or similar salts. If the compounds of the invention contain relatively basic functional groups, acid addition salts by contacting a sufficient amount of acid with the neutral form of the compound in pure solution or a suitable inert solvent. Can be obtained. Examples of pharmaceutically acceptable acid addition salts are hydrochloric acid, hydrobromic acid, nitrate, carbonic acid, bicarbonate ion, phosphoric acid, monohydrogen phosphate ion, dihydrogen phosphate ion, sulfuric acid, hydrogen sulfate ion, iodine. Inorganic acid salts containing inorganic acids such as hydrobromic acid and phosphite, and acetic acid, propionic acid, isobutyric acid, maleic acid, malonic acid, benzoic acid, succinic acid, suberic acid, fumaric acid, lactic acid, mandelic acid, Contains organic acid salts containing organic acids such as phthalic acid, benzenesulfonic acid, p-toluenesulfonic acid, citric acid, tartaric acid and methanesulfonic acid, as well as salts of amino acids (eg arginine), and glucron. Contains salts of organic acids such as acids. Certain compounds of the present invention can be converted to any one base or acid addition salt by including basic and acidic functional groups.

The pharmaceutically acceptable salt of the present invention can be synthesized from a parent compound containing an acid group or a base by a conventional chemical method. Under general circumstances, a method for producing such a salt is as follows. It is prepared by reacting these compounds in the form of free acids or free bases in water or organic solvents or mixtures of both with appropriate bases or acids in stoichiometry.

The compounds of the present invention may have specific geometric or steric isomer forms. The present invention relates to virtualized cis and trans isomers (-)-and (+)-pair enantiomers, (R)-and (S) -enantiomers, diastereomers, (D) -isomers, Includes all of the (L) -isomers, racemic mixtures thereof and other mixtures, such as mixtures enriched with enantiomers or diastereomers, all such mixtures are within the scope of the present invention. A separate asymmetric carbon atom can be present in the substituent such as alkyl. All such isomers and mixtures thereof are within the scope of the present invention.

Unless otherwise stated, the term "enantiomer" or "optical isomer" refers to a stereoisomer that is in a mirror image relationship with each other.

Unless otherwise stated, the term "cis-trans isomer" or "geometric isomer" refers to a double bond or a single bond of carbon atoms that make up a ring that is not free to rotate.

Unless otherwise stated, the term "diastereomers" refers to stereoisomers that have two or more chiral centers in a molecule and that are mirror images of each other between the molecules.

Unless otherwise stated, "(D)" or "(+)" represents right-handed rotation, "(L)" or "(-)" represents left-handed rotation, and "(DL)" or "( ±) ”represents a racemic body.

Wedge-shaped solid line connection unless otherwise stated

And wedge-shaped dashed line connection

Represents the absolute configuration of one stereocenter with, and straight solid line connection

And straight dashed line join

Represents the relative arrangement of the stereocenter with, and the wavy line

Wedge-shaped solid line connection

Or wedge-shaped dashed line connection

Or wavy line

Straight solid line connection

And straight dashed line connection

Represents.

The compounds of the present invention may exist in a particular form. Unless otherwise stated, the term "tautomer" or "tautomer morphology" means that different functional isomers are in dynamic equilibrium at room temperature and can be rapidly converted to each other. If tautomers are possible (such as in solution), chemical equilibrium of tautomers can be achieved. For example, proton tautomers (also known as prototropic tautomers) include interconversion by proton transfer, including, for example, keto-enol isomers and imine-enamine isomers. Valence tautomers involve the conversion of certain binding electrons into each other by reorganization. Among them, a specific example of keto-enol isomerism is the mutual conversion between two tautomers of pentane-1,4-dione and 4-hydroxypenta-3-en-2-one.

Unless otherwise stated, the terms "rich in one isomer", "rich in isomers", "rich in one enantiomer" or "rich in enantiomer" have a content of one isomer or enantiomer of 100. % And the content of the isomer or enantiomer is 60% or more, or 70% or more, or 80% or more, 90% or more, or 95% or more, or 96% or more, or 97% or more, or 98. % Or more, or 99% or more, or 99.5% or more, or 99.6% or more, or 99.7% or more, or 99.8% or more, or 99.9% or more.

Unless otherwise stated, the term "isomer excess" or "enantiomeric excess" refers to the difference in relative percentage between two isomers or the difference in relative percentage between two enantiomerics. For example, if the content of one isomer or enantiomeric is 90% and the content of the other isomer or enantiomeric is 10%, the isomer excess or enantiomeric excess (ee value) is 80%. Become.

Optically active (R)-and (S) -isomers and D and L isomers can be produced by chiral synthesis or chiral reagents or other conventional techniques. If one of the enantiomers of a compound of the present invention is to be obtained, it can be produced by an asymmetric synthesis or an inducing action of a chiral auxiliary, and the diastereomer mixture obtained here is separated and an auxiliary group is obtained. The corps splits to provide the required pure enantiomers. Alternatively, if the molecule contains a basic functional group (eg, amino group) or an acidic functional group (eg, carboxyl), after forming a salt of diastereomers with an acid or base of appropriate optically active activity, the art. The diastereomers are separated by a conventional method known to the above, and then recovered to obtain a pure enantiomer. In addition, the separation of enantiomers and diastereomers is usually completed by a chromatographic method, which uses a chiral stationary phase to optionally combine with a chemical induction method (eg, carbamate with an amine). To generate). The compound of the present invention may contain an unnatural proportion of atomic isotopes in one or more atoms constituting the compound. Compounds can be labeled using, for example, radioactive isotopes such as tritium (3H), iodine-125 (125I) or C-14 (14C). Also, for example, it is replaced by deuterium to form a deuterated drug. The bond composed of deuterium and carbon is stronger than the bond composed of ordinary hydrogen and carbon, and deuterated drugs reduce toxic side effects and drug stability compared to non-deuterated drugs. It has the advantage of increasing the amount of hydrogen, increasing the therapeutic effect, and extending the biological half-life of the drug. All isotopic conversions of the compounds of the invention, whether radioactive or not, are within the scope of the invention. "Arbitrary" or "arbitrarily" means that the incident or situation described after that may appear, but it does not have to appear mandatory, and the description is used when the incident or situation occurs, and Including the case where the above-mentioned incident or situation does not occur.

The term "substituted" means that any one or more hydrogen atoms on a particular atom have been substituted with a substituent, said hydrogen atom can include deuterium and hydrogen variants. It is sufficient that the valence state of a specific atom is normal and the compound after substitution is stable. When the substituent is an oxy group (that is, = O), it means that two hydrogen atoms have been substituted. Oxo substitutions do not occur with aryls. The term "arbitrarily replaced" means that it may or may not be replaced. Unless otherwise stated, the type and number of substituents may be arbitrary as long as they are chemically feasible.

Any variable (eg, R) is defined independently in any situation if it appears more than once in the composition or structure of the compound. Thus, for example, if one group is substituted with 0-2 Rs, the group may be optionally substituted with at most 2 Rs, and in any situation the Rs are independently selected. To. In addition, combinations of substituents and / or variants thereof are only allowed if the combination produces a stable compound.

When the number of one linking group is 0, for example, − (CRR) 0− indicates that the linking group is a single bond.

When one of the variables is selected from a single bond, it means that the two groups linked together are directly linked to each other, for example, L in A-L-Z is a single bond. When, it means that the structure is actually AZ.

When one substituent is vacant, it means that the substituent does not exist. For example, when X is vacant in AX, it means that the structure is really A. If it is not specified through which atom the substituents listed are attached to the group to be substituted, the substituents can be attached via any of the atoms, eg, pyridyl. Can be attached as a substituent to a group substituted via any one carbon atom on the pyridine ring. If the listed linking groups do not indicate the binding direction, the binding direction is arbitrary. For example

In, the linking group L is -MW-, in which case -MW- is connected to rings A and B in the same direction as the reading order from left to right.

May be configured by connecting to rings A and B in the opposite direction of the left-to-right reading order.

May be configured. The combination of linking groups, substituents and / or variants thereof is acceptable only if such a combination produces a stable compound.

Unless otherwise stated, the term "hetero" refers to a heteroatom or heteroatom (ie, an atom group containing a heteroatom), excluding carbon (C) and hydrogen (H), and such heteros. It contains an atomic group containing atoms, for example, oxygen (O), nitrogen (N), sulfur (S), silicon (Si), germanium (Ge), aluminum (Al), boron (B), -O-,-. S-, = O, = S, -C (= O) O-, -C (= O)-, -C (= S)-, -S (= O), -S (= O) 2-, And optionally substituted -C (= O) N (H)-, -N (H)-, -C (= NH)-, -S (= O) 2N (H)-or -S (= O) ) N (H)-includes.

Unless otherwise stated, "ring" represents substituted or unsubstituted cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, heterocycloalkynyl, aryl or heteroaryl. The ring includes a single ring, a ring assembly, a spiro ring, a fused ring or a crosslinked ring. The number of atoms in a ring is usually defined as the number of members of the ring, for example "5-7 membered ring" means that 5-7 atoms are enclosed and arranged. Unless otherwise stated, the ring optionally comprises 1-3 heteroatoms. Thus, the "5-7 membered ring" comprises, for example, phenyl, pyridine and piperidinyl, while the term "5-7 membered heterocycloalkyl ring" comprises pyridinyl and piperidinyl but not phenyl. The term "ring" further includes a ring system comprising at least one ring, where each "ring" independently meets the definition.

Unless otherwise stated, the term "heterocycle" or "heterocyclic group" refers to a stable monocycle, double ring or triple ring containing a heteroatom or heteroatom, which are saturated or partially unsaturated. , Or may be unsaturated (aromatic), which contain carbon atoms and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. Here, the arbitrary heterocycle can be fused to one benzene ring to form a double ring. Nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p, p are 1 or 2). The nitrogen atom can be substituted or unsubstituted (ie, N or NR, where R is H, or another substituent as defined in the text). The heterocycle can form a stable structure by being attached to a pendant group of any heteroatom or carbon atom. If the compound produced is stable, the heterocycles described in the text can undergo substitutions at carbon or nitrogen positions. Heterocyclic nitrogen atoms are arbitrarily quaternized. As a preferred strategy, if the total number of S and O atoms in the heterocycle exceeds 1, such heteroatoms are not adjacent to each other. Alternatively, the total number of S and O atoms in the heterocycle does not exceed one. As used in the text, the term "aromatic heterocyclic group" or "heteroaryl" is a stable 5,6,7-membered monocyclic or bicyclic, or 7,8,9 or 10-membered two. Refers to the aromatic ring of a heterocyclic group, which contains a carbon atom and 1, 2, 3 or 4 ring heteroatoms independently selected from N, O and S. The nitrogen atom can be substituted or unsubstituted (ie, N or NR, where R is H, or another substituent as defined in the text). Nitrogen and sulfur heteroatoms can be optionally oxidized (ie, NO and S (O) p, p are 1 or 2). It should be noted that the total number of S and O atoms in the aromatic heterocycle does not exceed 1. Crosslinked rings are also included in the definition of heterocycles. When one or more atoms (ie, C, O, N or S) connect two non-adjacent carbon or nitrogen atoms, a crosslinked ring is formed. Preferred crosslinked rings include, but are not limited to, one carbon atom, two carbon atoms, one nitrogen atom, two nitrogen atoms and one carbon-nitrogen group. It should be noted that one bridge always transforms a single ring into a triple ring. In a crosslinked ring, substituents on the ring can appear at the bridge.

Examples of heterocyclic compounds are acridinyl, azocinyl, benzimidazolyl, benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl, benzooxazollinyl, benzothiazolyl, benzotriazolyl, benzotetrazolyl, benzo. Isooxazolyl, benzoisothiazolyl, benzimidazolidinyl, carbazolyl, 4aH-carbazolyl, carborinyl, chromanyl, chromenyl, cinnolinyl, decalhydroquinolyl, 2H, 6H-1,5,2-dithiazinyl, dihydroflo [2,3] -B] Tetrahydrofuranyl, furanyl, frazanyl, imidazolidinyl, imidazolidinyl, imidazolyl, 1H-indazolyl, indolealkenyl, indolinyl, indridinyl, indrill, 3H-indrill, isobenzofuranyl, isoindrill, isoindolinyl, isoquinolyl, isothiazolyl, isoxazolyl Oxyphenyl, morpholinyl, naphthyldinyl, octahydroisoquinolyl, oxadiazolyl, 1,2,3-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl, oxazolyl , Indoxyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl, phenazinyl, phenothiazine, benzoxanthyl, phenoxadinyl, ptalradinyl, piperazinyl, piperidinyl, piperidonyl, 4-piperidinyl, piperonyl, pteridinyl, prynyl, pyrazinyl, pyrazolinyl , Pyrazolinyl, pyrazolyl, pyridadinyl, pyridooxazolyl, pyridoimidazolyl, pyridothiazolyl, pyridinyl, pyrrolidinyl, pyrrolinyl, 2H-pyrrolid, pyrrolyl, quinazolinyl, quinolyl, 4H-quinolidinyl, quinoxalinyl, quinuclidinyl, tetrahydrofuranyl, tetrahydroisoquinolyl , Tetrahydroquinolyl, tetrazolyl, 6H-1,2,5-thiadiazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thiantranyl , Thiazolyl, Isothiazolyl, Thienyl, Thienooxazolyl, Thienothiazolyl, Thienoimidazolyl, Thienyl, Triazinyl, 1H-1,2,3-triazolyl, 2H-1,2,3-triazolyl, 1H-1,2,4-tria Includes, but is not limited to, zoryl, 4H-1,2,4-triazolyl, and xanthenyl. Examples of heterocyclic compounds further include fused cyclic and spirocyclic compounds.

Unless otherwise stated, the term "hydrocarbon group" or its sub-concepts (eg, alkyl, alkenyl, alkynyl, phenyl, etc.) are linear, branched, as part of themselves or another substituent. Represents a chain or cyclic hydrocarbon atomic group or a combination thereof and can be fully saturated (eg, alkyl), monovalent or polyunsaturated (eg, alkenyl, alkynyl, phenyl), monosubstituted, It can be double- or poly-substituted and can be monovalent (eg, methyl), divalent (eg, methylene group) or polyvalent (eg, metenyl), divalent or polyvalent atom. Can contain groups and can contain a specified number of carbon atoms (eg C _1- C ₁₂ represents 1 to 12 carbons, C _1-12 are C ₁ , C ₂ , C ₃ , C ₄ , C. Selected from ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ; C _3-12 are C ₃ , C ₄ , C ₅ , C ₆ , C ₇ , C ₈ , C ₉ , C ₁₀ , C ₁₁ and C ₁₂ ). The "hydrocarbon group" includes, but is not limited to, an aliphatic hydrocarbon group and an aromatic hydrocarbon group, and the aliphatic hydrocarbon group includes chain-like and cyclic groups, and specifically, alkyl. The aromatic hydrocarbon groups include, but are not limited to, alkenyl and alkynyl, including, but are not limited to, 6-12 member aromatic hydrocarbon groups such as benzene and naphthalene. In some embodiments, the term "hydrocarbon group" represents a linear or branched chain atomic group or a combination thereof and can be fully saturated, monovalent or polyunsaturated. It can contain divalent and polyvalent atomic groups. Examples of saturated hydrocarbon atomic groups are methyl, ethyl, n-propyl, isopropyl, n-butyl, tert-butyl, isobutyl, sec-butyl, isobutyl, cyclohexyl, (cyclohexyl) methyl, cyclopropylmethyl and n-pentyl, Includes, but is not limited to, homologues or isomers of atomic groups such as n-hexyl, n-heptyl, n-octyl. Unsaturated alkyls have one or more double or triple bonds, examples of which are vinyl, 2-propenyl, butenyl, crotyl, 2-isopentenyl, 2- (butadienyl), 2,4-pentadienyl. , 3- (1,4-pentadienyl), ethynyl, 1-propynyl, 3-propynyl, 3-butenyl and higher homologues and isomers, but not limited to these.

Unless otherwise stated, the term "heterohydrocarbon group" or its sub-concepts (eg, heteroalkyl, heteroalkenyl, heteroalkynyl, heteroaryl, etc.), together with itself or another term, is constant. Represents a stable linear, branched or cyclic hydrocarbon atom group or a combination thereof formed by a number of carbon atoms and at least one heteroatom. In some embodiments, the term "heteroalkyl", in itself or in combination with another term, is a stable linear, branched chain formed by a certain number of carbon atoms and at least one heteroatom. Represents a chain hydrocarbon atomic group or a composition thereof. In one typical embodiment, the heteroatom is selected from B, O, N and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen heteroatom is optionally quaternized. The heteroatom or heteroatom group can be located at any internal position of the heterohydrocarbon group, including the position where the hydrocarbon group is attached to the rest of the molecule. However, the terms "alkoxy", "alkylamino" and "alkylthio" (or thioalkoxy) belong to idiomatic expressions and are alkyl groups linked to the rest of the molecule via one oxygen atom, amino or sulfur atom, respectively. Point to. Examples are -CH ₂ -CH _2- O-CH ₃ , -CH ₂ -CH _2- NH-CH ₃ , -CH ₂ -CH _2- N (CH ₃ ) -CH ₃ , -CH ₂ -SCH. _2- CH ₃ , -CH _2- CH ₂ , -S (O) -CH ₃ , -CH _2- CH _2- S (O) ₂ -CH ₃ , -CH = CH-O-CH ₃ , -CH ₂ Includes, but is not limited to, -CH = N-OCH ₃ and -CH = CH-N (CH ₃ ) -CH ₃ . At most two heteroatoms can be contiguous. For example, -CH _2- NH-OCH ₃ can be mentioned.

Unless otherwise stated, the terms "cyclohydrocarbon groups", "heterocyclohydrocarbon groups" or their subordinate concepts (eg, aryl, heteroaryl, cycloalkyl, heterocycloalkyl, cycloalkenyl, heterocycloalkenyl, cycloalkynyl, Heterocycloalkynyl, etc.), together with itself or another term, represents a cyclized "hydrocarbon group", "heterohydrocarbon group", respectively. In the case of a heterohydrocarbon group or a heterocyclohydrocarbon group (eg, heteroalkyl, heterocycloalkyl), the heteroatom can occupy the position where the heterocycle is attached to the rest of the molecule. Examples of cyclohydrocarbon groups include, but are not limited to, cyclopentyl, cyclohexyl, 1-cyclohexenyl, 3-cyclohexenyl, cycloheptyl and the like. Non-limiting examples of heterocyclo groups are 1- (1,2,5,6-tetrahydropyridyl), 1-piperidinyl, 2-piperidinyl, 3-piperidinyl, 4-morpholinyl, 3-morpholinyl, tetrahydrofuran-2-yl. , Tetrahydrofuran indole-3-yl, tetrahydrothiophene-2-yl, tetrahydrothiophene-3-yl, 1-piperazinyl and 2-piperazinyl.

Unless otherwise stated, the term "heterocycloalkyl", together with itself or other terms, refers to the "heteroalkyl" of cyclization. Also, in the case of the "heterocycloalkyl", the heteroatom can occupy the bond position of the heterocycloalkyl to the rest of the molecule. In some embodiments, examples of said heterocycloalkyl are azetidinyl, oxetanyl, thietanyl, pyrrolidinyl, pyrazolidinyl, imidazolidinyl, tetrahydrothienyl, tetrahydrofuranyl, tetrahydropyranyl, piperidinyl, piperazinyl, morpholinyl, dioxanyl, dithianyl, isoxalysyl. Includes, but is not limited to, dinyl, isothiazolidinyl, 1,2-oxadinyl, 1,2-thiazinyl, hexahydropyridazinyl, homopiperazinyl, homopiperidinyl or oxepanyl.

Unless otherwise described, the term "alkyl" denotes a straight-chain or branched-chain saturated hydrocarbon group, monosubstituted (e.g., -CH 2 _F) can be those that are or polysubstituted, It can be monovalent (eg, methyl group), divalent (eg, methylene group) or polyvalent (eg, methylidene group). Examples of alkyls include methyl (Me), ethyl (Et), propyl (eg n-propyl and isopropyl), butyl (eg n-butyl, isobutyl, s-butyl, t-butyl), pentyl (eg, eg). n-pentyl, isopentyl, neopentyl) and the like.

Unless otherwise stated, cycloalkyls may contain any stable cyclic or polycyclic hydrocarbon groups, all carbon atoms are saturated, monosubstituted or polysubstituted, and monovalent. It can be divalent or multivalent. Examples of these cycloalkyls include cyclopropyl, norbornenyl, [2.2.2] bicyclooctane, [4.4.0] bicyclodecane and the like.

Unless otherwise stated, the term "halogenation" or "halogen" refers to a fluorine, chlorine, bromine or iodine atom as itself or as part of another substituent. Also, the term "alkyl halogenated" includes monosubstituted alkyl halides or polysubstituted alkyl halides. For example, the term "halogenated _(C 1 -C ₄₎ alkyl" is meant to include trifluoromethyl, 2,2,2-trifluoroethyl, 4-chlorobutyl and 3-bromopropyl including such as, but not limited to. Unless otherwise stated, examples of alkyl halides include, but are not limited to, trifluoromethyl, trichloromethyl, pentafluoroethyl and pentachloroethyl.

"Alkoxy" represents the alkyl bonded via an oxygen crosslink and having a specific number of carbon atoms. Unless otherwise stated, C _1-6 alkoxy comprises C ₁ , C ₂ , C ₃ , C ₄ , C ₅ and C ₆ alkoxy. Examples of alkoxy include, but are not limited to, methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, n-pentyloxy and S-pentyloxy.

The term "aryl" represents a polyunsaturated aromatic hydrocarbon substituent, which can be mono- or poly-substituted, can be monovalent, divalent or polyvalent, and can be monovalent, divalent or polyvalent. This can be monocyclic or polycyclic (eg, there are 1 to 3 rings, but at least one ring is an aromatic ring), which are fused or covalent. It is connected by a bond. The term "heteroaryl" refers to an aryl (or ring) containing 1 to 4 heteroatoms. In one exemplary example, the heteroatom is selected from B, N, O and S, where the nitrogen and sulfur atoms are optionally oxidized and the nitrogen atoms are optionally quaternized. Heteroaryl is linked to the rest of the molecule via a heteroatom. Non-limiting examples of aryl or heteroaryl include phenyl, naphthyl, biphenyl, pyrrolyl, pyrazolyl, imidazolyl, pyrazinyl, oxazolyl, phenyl-oxazolyl, isooxazolyl, thiazolyl, frill, thienyl, pyridyl, pyrimidinyl, benzthiazolyl, prynyl, benz. Imidazolyl, indrill, isoquinolyl, quinoxalinyl, quinolyl, 1-naphthyl, 2-naphthyl, 4-biphenyl, 1-pyrrolill, 2-pyrrolill, 3-pyrrolill, 3-pyrazolyl, 2-imidazolyl, 4-imidazolyl, pyrazinyl, 2- Oxazolyl, 4-oxazolyl, 2-phenyl-4-oxazolyl, 5-oxazolyl, 3-isooxazolyl, 4-isooxazolyl, 5-isooxazolyl, 2-thiazolyl, 4-thiazolyl, 5-thiazolyl, 2-furyl, 3-frill, 2-Thienyl, 3-thienyl, 2-pyridyl, 3-pyridyl, 4-pyridyl, 2-pyrimidinyl, 4-pyrimidinyl, 5-benzthiazolyl, prynyl, 2-benzimidazolyl, 5-indrill, 1-isoquinolyl, 5-isoquinolyl , 2-Kinoxalinyl, 5-Kinoxalinyl, 3-quinolyl and 6-quinolyl. The substituent of any one aryl and heteroaryl ring system is selected from the acceptable substituents described below in the text.

Unless otherwise stated, aryl, when used in combination with other terms (eg, aryloxy, arylthio, aralkyl), includes aryl and heteroaryl rings as defined above. Thus, the term "aralkyl" includes atomic groups of aryl attached to alkyl (eg, benzyl, phenylethyl, pyridinemethyl, etc.), such as phenoxymethyl, 2-pyridineoxymethyl, 3- (1-naphthaleneoxy). It means that a carbon atom (for example, a methylene group) such as propyl contains an alkyl already substituted with an atom such as an oxygen atom.

The term "leaving group" refers to a functional group or atom that can be substituted through a substitution reaction (eg, a nucleophilic substitution reaction) by another type of functional group or atom. For example, typical leaving groups are trifluoromethanesulfonate; chlorine, bromine, iodine; methanesulfonate, tosylate, p-bromobenzenesulfonate, p-toluenesulfonate, etc., and sulfonate groups; acetoxy, trifluoroacetoxy, etc. Contains acyloxy.

The term "protecting group" includes, but is not limited to, "amino protecting group", "hydroxy protecting group" or "thiol protecting group". The term "amino protecting group" refers to a protecting group suitable for blocking side reactions at the nitrogen moiety of an amino group. Representative amino protecting groups are formil groups; acyls such as alkanoyl groups (eg, acetyl, dichloroacetyl or trifluoroacetyl); alkoxycarbonyls such as tert-butoxycarbonyl (Boc); benzyloxycarbonyl (Cbz). ), Arylmethoxycarbonyl such as 9-fluorenylmethoxycarbonyl (Fmoc); arylmethyl such as benzyl (Bn), trityl (Tr), 1,1-bis- (4'-methoxyphenyl) methyl; trimethylsilyl Includes, but is not limited to, silyls such as (TMS) and tert-butyldimethylsilyl (TBS). The term "hydroxy protecting group" refers to a protecting group suitable for blocking a side reaction of hydroxy. Typical hydroxy protecting groups are alkyl such as methyl, ethyl and tert-butyl; acyls such as alkanoyl groups (eg acetyl); benzyl (Bn), p-methoxybenzyl (PMB), 9-fluorenylmethyl. (Fm) and arylmethyls such as diphenylmethyl (diphenylmethyl, DPM); including, but not limited to, silyls such as trimethylsilyl (TMS) and tert-butyldimethylsilyl (TBS).

The compound of the present invention can be produced by various synthetic methods familiar to those skilled in the art, and the following specific embodiments, embodiments in combination with other chemical synthesis methods, and those skilled in the art Preferred embodiments include, but are not limited to, examples of the present invention, including familiar equivalents.

The compounds of the present invention have many uses or indications, including, but not limited to, the specific uses or indications listed in the present application.

The solvent used in the present invention is commercially available. The present invention uses the following abbreviations. aq represents water; HATU represents O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate; EDC represents N- (3-dimethyl). Aminopropyl) -N'-ethylcarbodiimide hydrochloride; m-CPBA represents 3-chloroperoxybenzoic acid; eq represents equivalents, equal amounts; CDI represents carbonyldiimidazole; DCM represents dichloromethane; PE stands for petroleum ether; DIAD stands for diisopropyl azodicarboxylate; DMF stands for N, N-dimethylformamide; DMSO stands for dimethylsulfoxide; EtOAc stands for ethyl acetate; EtOH stands for ethanol; MeOH stands for methanol. CBz stands for benzyloxycarbonyl and is one of the protecting groups for amines; BOC stands for tert-butylcarbonyl and is one of the protecting groups for amines; HOAc stands for acetic acid; NaCNBH ₃ stands for cyanohydrogenation. Represents sodium boron; r. t. Represents room temperature; O / N represents overnight; THF represents tetrahydrofuran; Boc ₂ O represents di-tert-butyl dicarbonate; TFA represents trifluoroacetic acid; DIPEA represents diisopropylethylamine; SOCl ₂ represents thionyl chloride; CS ₂ represents carbon disulfide; TsOH represents p-toluenesulfonic acid; NFSI represents N-fluoro-N- (phenylsulfonyl) benzenesulfonimide; NCS represents N-chloro N-Bu ₄ NF represents tetra-n-butylammonium fluoride; iPrOH represents 2-propanol; mp represents the melting point; LDA represents lithium diisopropylamide; EDCI represents 1- (3-) Didimethylaminopropyl) -3-ethylcarbodiimide hydrochloride; TEA represents triethylamine; DIEA represents N, N-diisopropylethylamine; ACN represents acetonitrile; IPA represents isopropanol; Pd (dppf) Cl2 is 1 , 1'-Bisdiphenylphosphinoferrocene represents palladium dichloride.

Compounds are named by hand or by ChemDraw® software, and commercially available compounds use the distributor's catalog name.

The compounds of the present invention are capable of sufficiently inhibiting PI3K kinase activity and at the same time have high subtype selectivity for PI3Kβ / γ / δ; they also have high levels of phosphorylation of Akt downstream of PI3K in cells. It was able to inhibit well and also showed high subtype selectivity at the cellular level. The compounds of the present invention can clearly inhibit tumor growth in vivo and also exhibit a clear time-dependent and dose-dependent inhibitory effect on Akt phosphorylation levels downstream of PI3K in vivo in animals. The compounds of the present invention have no significant inhibitory effect on hERG and CYP enzymes and are metabolically stable in human, rat, mouse, canine and monkey hepatocytes.

[Mode for carrying out the invention]
The present invention will be described in detail below based on examples, but does not imply any disadvantageous limitation to the present invention. Although the text describes the invention in detail and discloses specific embodiments thereof, various modifications to the specific embodiments of the present invention will be made to those skilled in the art as long as they do not deviate from the purpose and scope of the invention. And it is self-evident that improvements may be made.
Reference example 1: Fragment BB-1

Step 1: Synthesis of Compound BB1-2 Compound BB1-1 (20.00 g, 92.58 mmol) was added to dichlorosulfoxide (110.14 g, 925.79 mmol, 67.16 mL), and the mixture was stirred at 80 ° C. for 2 hours. The dichlorosulfoxide was then removed under reduced pressure, the residue was dissolved in tetrahydrofuran (550 mL) and the system was introduced with ammonia at 0 ° C. for 30 minutes. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent to obtain compound BB1-2, which was used as it was in the next reaction.

Step 2: Synthesis of compound BB-1.

Compound BB1-2 (20 g) and formamidine acetate (19.36 g, 186.01 mmol) were added to ethanol (800 mL) and the system was stirred at 80 ° C. for 16 hours. After completion of the reaction, ethanol was removed under reduced pressure, diluted with water (500 mL) and filtered to give compound BB-1. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.20 (d, J = 2.5 Hz, 1 H), 8.14 (s, 1 H), 7.96 (dd, J = 8.8, 2.3 Hz, 1 H), 7.63 (d, J = 8.5 Hz, 1 H).

Reference example 2: Fragment BB-2

Step 1: Synthesis of compound BB2-2.

Compound BB2-1 (20.00 g, 176.82 mmol, 18.87 mL), methyl iodide (37.65 g, 265.23 mmol, 16.51 mL), potassium carbonate (48.88 g, 353.64 mmol) were added to DMF (100 mL) to formulate 25 The mixture was stirred at ° C. for 48 hours. After completion of the reaction, the solvent is removed under reduced pressure, diluted with water (200 mL), extracted with methylene chloride (200 mL), the organic phase is concentrated under reduced pressure and the residue is chromatographic column (ethyl acetate: petroleum ether). Separation was performed by (= 0% to 15%) to obtain compound BB2-2. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ: 4.23 --4.34 (m, 2 H), 3.56 (q, J = 7.4 Hz, 1 H), 1.61 (dd, J = 7.5, 1.5 Hz, 3 H), 1.31 --1.37 (m, 3 H).

Step 2: Synthesis of compound BB2-3.

Compound BB2-2 (2.30 g, 18.09 mmol) was dissolved in ethanol (20.00 mL), then Runny Nickel (1.55 g, 18.09 mmol) was added under a stream of nitrogen gas to make the system under 50 Pa hydrogen gas pressure. , Stirred at 25 ° C. for 24 hours. After completion of the reaction, the system was filtered, the filtrate was concentrated under reduced pressure, and the residue was separated by a chromatography column (methanol: methylene chloride = 0% to 6%) to obtain compound BB2-3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 4.01 --4.09 (m, 2 H), 2.72 (dd, J = 12.5, 7.0 Hz, 1 H), 2.55 --2.62 (m, 1 H), 2.35 --2.45 (m, 1 H), 1.18 (t, J = 7.3 Hz, 3 H), 1.04 (d, J = 7.0 Hz, 3 H).

Step 3: Synthesis of compound BB2-5.

Compound BB2-4 (1.20 g, 5.55 mmol), Compound BB2-3 (800 mg, 6.11 mmol), EDCI (1.09 g, 5.66 mmol), 2-hydroxypyridin-N-oxide (722 mg, 6.49 mmol), triethylamine (2.25). g, 22.20 mmol, 3.08 mL) was added to methylene chloride (120 mL) and the system was stirred at 50 ° C. for 16 hours. After completion of the reaction, the reaction mixture is diluted with water (200 mL), extracted with methylene chloride (200 mL), the organic phase is concentrated under reduced pressure, and the residue is collected on a chromatography column (methanol: methylene chloride = 0% to 2%). ) To give compound BB2-5. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 8.46 (t, J = 5.6 Hz, 1 H), 7.61 (d, J = 2.3 Hz, 1 H), 7.26 (dd, J = 8.8, 2.3 Hz) , 1 H), 6.67 (d, J = 8.8 Hz, 1 H), 6.52 (br s, 2 H), 4.06 (q, J = 7.1 Hz, 2 H), 3.37 --3.45 (m, 1 H), 3.21 --3.29 (m, 1 H), 2.67 --2.80 (m, 1 H), 1.17 (t, J = 7.2 Hz, 3 H), 1.08 (d, J = 7.0 Hz, 3 H).

Step 4: Synthesis of Compound BB-2 Compound BB2-5 (1.00 g, 2.86 mmol) was added to formic acid (24.40 g, 530.09 mmol, 20.00 mL) and the system was stirred at 100 ° C. for 16 hours. After completion of the reaction, the reaction mixture was concentrated under reduced pressure, and the residue was separated by a chromatography column (ethyl acetate: petroleum ether = 0% to 40%) to obtain compound BB-2. MS-ESI m / z: 340.8 [M + H] ⁺ .

Reference example 3: Fragment BB-3

Step 1: Synthesis of Compound BB-3 Compound BB-3-1 (10.00 g, 39.98 mmol) is dissolved in pyridine (20 mL), which is further dissolved in Compound BB-3-2 (9.16 g, 39.98 mmol, 5.83 mL). ) Was added, and the mixture was stirred at 25 ° C. for 16 hours. The reaction mixture was spin-dried, diluted with water (200 mL), extracted with ethyl acetate (200 mL), and the organic phase was spin-dried to give the target compound BB-3.

Reference example 4: Fragment BB-4

Step 1: Synthesis of compound BB-4-3 Compound BB-4-1 (200 mg, 1.07 mmol) was dissolved in pyridine (5.00 mL), and compound BB-4-2 (245 mg, 1.07 mmol, 156.00) was dissolved therein. μL) was added dropwise, and the mixture was stirred at 25 ° C. for 16 hours. After completion of the reaction, the reaction solution was spin-dried to obtain the target compound BB-4-3.

Step 2: Synthesis of Compound BB-4 Compound BB-4-3 (400 mg, 1.05 mmol), Compound BB-4-4 (400 mg, 1.58 mmol), Potassium Acetate (207 mg, 2.11 mmol), Pherocene chloride (Pallace chloride) 77 mg, 105.23 μmol) was dissolved in dioxane (12 mL), and the reaction solution was stirred at 100 ° C. for 16 hours under the protection of nitrogen gas. The reaction mixture was diluted with water (100 mL), further extracted with methylene chloride (100 mL × 2), and the organic phase was rotationally dried to obtain the target compound BB-4.

Reference example 5: Fragment BB-5

Step 1: Synthesis of Compound BB-5-2 Compound BB-5-1 (10.00 g, 88.35 mmol) is dissolved in chlorosulfonic acid (35.00 g, 300.39 mmol, 20.00 mL) at room temperature for 18 hours at 140 ° C. Stirred. The reaction mixture was cooled to 30 ° C., phosphorus pentachloride (36.80 g, 176.70 mmol) was added in portions to the reaction solution, and the reaction solution was stirred at 110 ° C. for 1 hour. Cool the reaction solution to 30 ° C., add ice water (100 mL) to the reaction solution drop by drop, extract with methylene chloride (100 mL × 5), wash the organic phase with water (100 mL × 3), and remove the organic phase. , Anhydrous sodium sulfate was dried, and the organic phase was rotationally dried to obtain the target compound BB-5-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.75 (s, 3 H), 2.73 (s, 3 H), 2.72 --2.74 (m, 1 H).

Step 2: Synthesis of compound BB-5-4
Compound BB-5-2 (265 mg, 1.42 mmol) was dissolved in pyridine (1.00 mL) at 25 ° C, further compound BB-5-3 (300 mg, 1.42 mmol) was added thereto, and 16 at 25 ° C. Stirred for hours. The reaction was spin-dried and TLC (petroleum ether: ethyl acetate = 2: 1) showed that new points were generated. Purification by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 1: 1) gave the target compound BB-5-4. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 8.40 (d, J = 2.0 Hz, 1 H), 7.89 (d, J = 2.0 Hz, 1 H), 2.65 (s, 3 H), 2.45 (s, 3 H), 2.30 --2.34 (m, 3 H).

Step 3: Synthesis of Compound BB-5 Compound BB-5-4 (300 mg, 828.11 μμmol), Compound BB-5-5 (315 mg, 1.24 mmol), Potassium Acetate (243 mg, 2.48 mmol), Ferrocene Palladium Chloride (61 mg, 83.37 μmol) was dissolved in dioxane (12 mL), and the reaction solution was stirred at 100 ° C. for 1 hour under the protection of nitrogen gas. The reaction mixture was diluted with water (100 mL), further extracted with methylene chloride (100 mL), and the organic phase was rotationally dried to obtain the target compound BB-5.

Reference example 6: Fragment BB-6

Step 1: Synthesis of compound BB-6-1
A solution of 3-amino-5-bromopyridine (200 mg, 1.16 mmol) and 2-chloro-4-fluorobenzenesulfonyl chloride (265 mg, 1.16 mmol) in pyridine (1 mL) was stirred at 15 ° C. for 16 hours. After completion of the reaction, the mixture was directly rotated and dried. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic phase was concentrated under reduced pressure and purified by column chromatography (MeOH: DCM = 0% to 10%) to give BB-6-1. MS-ESI m / z: 364.7 [M + H] ⁺ , 366.7 [M + H + 2] ⁺ .

Step 2: Synthesis of compound BB-6
BB-6-1 (320 mg, 875.25 μmol), bis (pinacolato) diboron (333 mg, 1.31 mmol), potassium acetate (258 mg, 2.63 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] A suspension of dioxane (20 mL) of dichloropalladium (II) (64 mg, 87.47 μmol) was replaced with nitrogen gas three times, after which the reaction was heated to 100 ° C. for 16 hours under nitrogen gas protection. Stirred. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurryed with water (100 mL), washed, and then extracted with methylene chloride (100 mL). The organic phase was concentrated under reduced pressure to give BB-6. MS-ESI m / z: 330.8.

Reference example 7: Fragment BB-7

Step 1: Synthesis of Compound BB-7-2 Compound BB-7-1 (10.00 g, 88.35 mmol) is dissolved in chlorosulfonic acid (35.00 g, 300.39 mmol, 20.00 mL) at room temperature for 18 hours at 140 ° C. Stirred. The reaction mixture was cooled to 30 ° C., phosphorus pentachloride (36.80 g, 176.70 mmol) was added in portions to the reaction solution, and the reaction solution was stirred at 110 ° C. for 1 hour. Cool the reaction solution to 30 ° C., add ice water (100 mL) to the reaction solution drop by drop, extract with methylene chloride (100 mL × 5), wash the organic phase with water (100 mL × 3), and remove the organic phase. , Anhydrous sodium sulfate was dried, and the organic phase was rotationally dried to obtain the target compound BB-7-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 2.75 (s, 3 H), 2.73 (s, 3 H), 2.72 --2.74 (m, 1 H).

Step 2: Synthesis of compound BB-7-4 Compound BB-7-2 (1.2 g, 5.47 mmol) and compound BB-7-3 (1.02 g, 5.47 mmol) were dissolved in pyridine (5 mL) at 15 ° C. Was stirred for 16 hours. The reaction mixture was diluted with water (30 mL), further extracted with methylene chloride (30 mL × 2), and the organic phase was rotationally dried to obtain the target compound BB-7-4.

Step 3: Synthesis of compound BB-7 Compound BB-7-4 (2.10 g, 5.43 mmol), compound BB-7-5 (2.07 g, 8.14 mmol), potassium acetate (1.6 g, 16.30 mmol), ferrocene palladium chloride (0.4 g, 546.67 μmol) was dissolved in dioxane (80 mL), and the reaction solution was stirred at 105 ° C. for 16 hours under the protection of nitrogen gas. The reaction mixture was diluted with water (30 mL), further extracted with methylene chloride (30 mL × 2), and the organic phase was rotationally dried to obtain the target compound BB-7.

Reference example 8: Fragment BB-8

Step 1: Synthesis of Compound BB-8-3 Compound BB-8-1 (3.00 g, 16.04 mmol) is dissolved in pyridine (10 mL), which is further dissolved in Compound BB-8-2 (3.67 g, 16.04 mmol, 2.34 mL) was added slowly and stirred at 25 ° C. for 16 hours. The reaction was spin-dried and TLC (petroleum ether: ethyl acetate = 2: 1) showed that new points were formed. Purification by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 10: 3) gave the target compound BB-8-3.

Step 2: Synthesis of compound BB-8 Compound BB-8-3 (5.50 g, 12.87 mmol), compound BB-8-4 (4.90 g, 19.30 mmol), potassium acetate (3.76 g, 38.35 mmol), ferrocene palladium chloride (941.00 mg, 1.29 mmol) was dissolved in dioxane (200 mL) and the reaction was stirred at 100 ° C. for 16 hours under nitrogen gas protection. The reaction mixture was diluted with water (200 mL), further extracted with methylene chloride (200 mL), and the organic phase was rotationally dried to obtain the target compound BB-8.

Reference example 9: BB-9

Step 1: Synthesis of compound BB-9-1
A solution of 3-amino-5-bromopyridine (200 mg, 1.16 mmol) and 2,4-dimethyl-1,3-thiazole-5-sulfonyl chloride (366 mg, 1.73 mmol) in pyridine (1 mL) at 15 ° C. Stirred for 16 hours. After completion of the reaction, the mixture was directly rotated and dried. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic phase was concentrated under reduced pressure to give BB-9-1. MS-ESI m / z: 347.8 [M + H] ⁺ , 349.8 [M + H + 2] ⁺ .

Step 2: Synthesis of compound BB-9
BB-9-1 (0.3 g, 838.13 μmol, purity: 97.29%), bis (pinacolato) diboron (0.319 g, 1.26 mmol), potassium acetate (0.247 g, 2.52 mmol) and [1,1'-bis (diphenyl) Phosphino) ferrocene] A suspension of dioxane (20 mL) of dichloropalladium (II) (0.061 g, 83.37 μmol) was replaced with nitrogen gas three times, after which the reaction solution was brought to 100 ° C. under nitrogen gas protection. It was heated and stirred for 16 hours. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurryed with water (50 mL), washed and then extracted with methylene chloride (50 mL). The organic phase was concentrated under reduced pressure to give BB-9. MS-ESI m / z: 313.9.

Reference example 10: Fragment BB-10

Step 1: Synthesis of compound BB-10-1
At 15 ° C., 2,4-dimethylthiazole (2.00 g, 17.67 mmol) was added to a solution of chlorosulfonic acid (7.00 g, 60.08 mmol). The reaction mixture was stirred at 140 ° C. and reacted for 18 hours. Then, the mixture was cooled to 30 ° C., phosphorus pentachloride (7.36 g, 35.34 mmol) was added thereto in portions, and the mixture was stirred at 110 ° C. and reacted for 1 hour. After completion of the reaction, the mixture was cooled to 30 ° C. and then added dropwise to the stirred ice-water mixture (50 mL). Then, it was extracted 3 times with methylene chloride (50 mL). The organic phase was distilled under reduced pressure, separated and purified by column chromatography (ethyl acetate: petroleum ether = 0%, 5%, 10%) to obtain the target compound BB-10-1. MS-ESI m / z: 211.7 [M + H] ⁺ .

Step 2: Synthesis of compound BB-10
BB-10-1 (1.80 g, 8.50 mmol) was added dropwise to a pyridine (4 mL) solution of BB-10-2 (2.13 g, 8.50 mmol) at 5 ° C. within 10 minutes. The reaction was stirred at 5 ° C. for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain BB-10, which was used as it was in the next step. MS-ESI m / z: 426.0 [M + H] ⁺ .

Control example 1: R001

Step 1: Synthesis of Compound R001-1 N, N-dimethylformamide of compound BB-1 (1.00 g, 4.44 mmol), ethyl 4-bromobutyrate (952 mg, 4.88 mmol) and cesium carbonate (2.17 g, 6.66 mmol) It was dissolved in methyl acetal (15 mL), heated to 60 ° C., and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (10 mL), and extracted with methylene chloride (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound R001-1 (MS-ESI m / z: 340.80 [M + H] ⁺ , 342.8 [M + H + 2]. ⁺ .

Step 2: Synthesis of Compound R001 Compound R001-1 (1.00 g, 2.95 mmol), BB-3 (1.31 g, 2.95 mmol), potassium acetate (1.16 g, 11.80 mmol) in dioxane (10 mL) and water (1 mL) ), Then ferrocene dichloride palladium (43.15 mg, 59.00 μmol) was added, and the mixture was heated to 95 ° C. under the protection of nitrogen gas and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (100 mL), and extracted with methylene chloride (100 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure, and the mixture was separated by an HPLC preparative column to obtain the target compound R001. ^{1 1} H NMR (400MHz, CDCl ₃ ) δ: 8.34 (d, J = 1.8 Hz, 1H), 8.21 --8.10 (m, 2H), 8.07 (s, 1H), 7.97 (d, J = 2.3 Hz, 1H) , 7.91 --7.82 (m, 1H), 7.82 --7.74 (m, 1H), 7.25 (br d, J = 2.5 Hz, 1H), 7.18 --7.05 (m, 1H), 4.21 --4.07 (m, 4H), 3.98 (s, 3H), 2.53 --2.35 (m, 2H), 2.16 (quin, J = 7.0 Hz, 2H), 1.27 (t, J = 7.2 Hz, 3H). MS-ESI m / z: 574.9.0 [M + H] ⁺ , 376.9. [M + H + 2] ⁺ .

Control example 2: R002, R003

Step 1: Synthesis of Compounds R002 and R003 Compound WX064-2 is supercritical fluid chromatography (separation condition column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: Separation by 40% -40%) gave enantiomers R002 and R003. The retention times were 2.802 min and 2.259 min, respectively, and the proportion was 1: 1. R002: ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 12.55 (br s, 1H), 10.26 (br s, 1H), 8.46 --8.32 (m, 2H), 8.25 (d, J = 2.3 Hz, 1H) ), 8.09 (dd, J = 2.3, 8.5 Hz, 1H), 8.01 --7.87 (m, 1H), 8.03 --7.87 (m, 1H), 8.02 --7.63 (m, 2H), 7.36 (dt, J = 2.5) , 8.5 Hz, 1H), 4.27 --4.13 (m, 1H), 4.11 --4.02 (m, 1H), 3.70 (s, 3H), 3.04 --2.92 (m, 1H), 1.14 (d, J = 7.3 Hz, 3H). MS-ESI m / z: 547.0 [M + H] ⁺ , 549.0 [M + H + 2] ⁺ . R003: ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.42 --8.33 (m, 2H), 8.25 (d, J = 2.3 Hz, 1H), 8.09 (dd, J = 2.3, 8.5 Hz, 1H), 7.96 (dd, J = 5.9, 8.9 Hz, 1H), 7.91 (d, J = 2.3 Hz, 1H), 7.82 --7.69 (m, 2H), 7.36 (dt, J = 2.5, 8.5 Hz, 1H), 4.22 --4.01 (m, 2H), 3.70 (s, 3H), 3.04 --2.90 (m, 1H), 1.14 (d, J = 7.3 Hz, 3H). MS-ESI m / z: 547.0 [M + H] ⁺ , 549.0 [M + H + 2] ⁺ .

Control example 3: R004, R005

Step 1: Synthesis of Compound R004-1 Compound BB-2 (10.00 g, 29.48 mmol) and lithium hydroxide monohydrate (12.37 g, 294.80 mmol) are dissolved in ethanol (50 mL) and water (50 mL). The mixture was stirred at 10 ° C. for 16 hours. TLC (methylene chloride: methanol = 10: 1) showed that new points were generated. Adjust the reaction solution to pH = 3-4 with hydrochloric acid (4 mol / L), then dilute the mixture with water (200 mL), extract with ethyl acetate (200 mL x 2), and spin dry the organic phase. The target compound R004-1 was obtained.

Step 2: Synthesis of Compound R004-2 Compound R004-1 (1.00 g, 3.21 mmol) is dissolved in dichlorosulfoxide (1.64 g, 13.78 mmol, 1.00 mL) and methanol (20 mL) at 60 ° C. under nitrogen gas protection. Stirred for 6 hours. TLC (petroleum ether: ethyl acetate = 10: 1) showed that new points were generated. The reaction mixture was spin-dried, after which the mixture was diluted with water (50 mL), extracted with ethyl acetate (50 mL x 3), the organic phase was dried over anhydrous sodium sulfate, and the organic phase was spin-dried. Purification was carried out by a silica gel column (petroleum ether: ethyl acetate = 5: 1-5: 3) to obtain the target compound R004-2. ¹ H NMR (400 MHz, CHLOROFORM-d) δ: 1.30 (d, J = 7.53 Hz, 3 H) 3.17 (dqd, J = 9.32, 7.27, 7.27, 7.27, 5.02 Hz, 1 H) 3.66 (s, 3 H) 4.02 (dd, J = 13.55, 9.03 Hz, 1 H) 4.18 (dd, J = 13.55, 5.02 Hz, 1 H) 7.58 (d, J = 8.53 Hz, 1 H) 7.83 (dd, J = 8.78, 2.26 Hz, 1 H) 8.12 (s, 1 H) 8.42 (d, J = 2.51 Hz, 1 H).

Step 3: Synthesis of compound R004-3 Compound R004-2 (150 mg, 461.32 μmol), compound BB-3 (200 mg, 451.77 μmol), potassium acetate (180 mg, 1.83 mmol), ferrocene palladium chloride (33 mg,) 45.10 μmol) was dissolved in dioxane (8 mL) and water (1.5 mL), and the reaction solution was stirred at 100 ° C. for 30 minutes under the protection of nitrogen gas. TLC (methylene chloride: methanol = 10: 1) showed that new points were generated. The reaction mixture was rotationally dried, further diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was taken, washed with saturated brine, and the organic phase was dried over anhydrous sodium sulfate. The organic phase was spin-dried, and further separated and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain the target compound R004-3.

Step 4: Synthesis of Compounds R004 and R005 Supercritical fluid chromatography of compound R004-3 (separation condition column: chromatography column: OJ (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B%: 40% -40%) separated to give enantiomers R004 and R005. R004: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 1.15 (d, J = 7.03 Hz, 3 H) 3.07 (sxt, J = 7.18 Hz, 1 H) 3.57 (s, 3 H) 3.69 (s , 3 H) 4.04 ―― 4.24 (m, 2 H) 7.32 ―― 7.40 (m, 1 H) 7.70 ―― 7.79 (m, 2 H) 7.91 (d, J = 2.26 Hz, 1 H) 7.96 (dd, J = 8.91 , 5.90 Hz, 1 H) 8.08 (dd, J = 8.41, 1.63 Hz, 1 H) 8.24 (d, J = 2.01 Hz, 1 H) 8.37 (s, 1 H) 8.39 (d, J = 2.01 Hz, 1 H). R005: ¹ H NMR (400 MHz, DMSO-d6) δ: 1.15 (d, J = 7.03 Hz, 3 H) 3.07 (sxt, J = 7.13 Hz, 1 H) 3.57 (s, 3 H) 3.69 (s, 3 H) 4.04 --4.25 (m, 2 H) 7.36 (td, J = 8.41, 2.51 Hz, 1 H) 7.69 --7.80 (m, 2 H) 7.91 (d, J = 2.26 Hz, 1 H) 7.96 (dd) , J = 8.78, 6.02 Hz, 1 H) 8.08 (dd, J = 8.53, 2.01 Hz, 1 H) 8.24 (d, J = 2.01 Hz, 1 H) 8.37 (s, 1 H) 8.40 (d, J = 2.26 Hz, 1 H). The retention times were 1.548 min and 1.782 min, respectively, and the proportion was 1: 1.

Control example 4: R006, R007

Step 1: Synthesis of compound R006-1 Compound R004-2 (350 mg, 1.08 mmol), compound BB-8 (400 mg, 1.16 mmol), potassium acetate (460 mg, 4.69 mmol), ferrocene palladium chloride (85 mg, 116.17 μmol) was dissolved in dioxane (15 mL) and water (3 mL), and the reaction solution was stirred at 100 ° C. for 30 minutes under the protection of nitrogen gas. TLC (methylene chloride: methanol = 10: 1) showed that new points were generated. The reaction mixture was spin-dried, further diluted with water (20 mL), extracted with ethyl acetate (10 mL × 2), the organic phase was taken, washed with saturated brine (20 mL), and the organic phase was anhydrous sodium sulfate. The organic phase was spin-dried, separated and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain the target compound R006-1.

Step 2: Synthesis of Compounds R006 and R007 Supercritical Fluid Chromatography of Compound R006-1 (Separation Condition Column: OD (250 mm * 30 mm, 10 μm); Mobile Phase: [0.1% NH ₃ H ₂ O EtOH]; B%: Separation by 35% -35%) gave enantiomers R006 and R007. R006: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (d, J = 7.28 Hz, 3 H) 2.37 (s, 3 H) 3.01 --3.13 (m, 1 H) 3.57 (s, 3 H) ) 4.05 --4.24 (m, 2 H) 7.37 (td, J = 8.47, 2.38 Hz, 1 H) 7.71 --7.81 (m, 3 H) 7.98 (dd, J = 8.78, 6.02 Hz, 1 H) 8.06 (dd) , J = 8.53, 2.01 Hz, 1 H) 8.21 (d, J = 2.01 Hz, 1 H) 8.38 (s, 1 H) 8.64 (br s, 1 H). R007: ¹ H NMR (400 MHz, DMSO- d ₆ ) δ ppm 1.15 (br d, J = 7.03 Hz, 3 H) 2.37 (br s, 3 H) 3.07 (br d, J = 7.53 Hz, 1 H) 3.57 (s, 3 H) 4.05 --4.25 (m, 2 H) 7.32 --7.42 (m, 1 H) 7.69 --7.84 (m, 3 H) 7.93 --8.02 (m, 1 H) 8.06 (br d, J = 8.53 Hz, 1 H) 8.21 (br s, 1 H) 8.38 (s, 1 H) 8.64 (br s, 1 H). The retention times were 1.413 min and 1.561 min, respectively, and the proportion was 1: 1.

Control example 5: R008

Step 1: Synthesis of compound R008-2.

Compound R008-1 (0.65 g, 1.64 mmol), methyl iodide (465 mg, 3.28 mmol, 204.22 μL) and tetrahydrofuran (6 mL) were added in this order to a pre-dried reaction bottle (8 mL), and finally lithium bis. (Trimethylsilyl) amide (1 M, 4.10 mL) was added slowly. It was then replaced with nitrogen gas and stirred at 15 ° C. for 10 hours. After completion of the reaction, the reaction mixture is quenched with methanol (10 mL), the solvent is then removed under reduced pressure, separated by flash column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1: 1), and purified. , Further purified by preparative HPLC. Purification method: Chromatography column: Agela Durashell C18 150 * 25mm 5μm; Mobile phase: [Water (10mM NH4HCO3) -ACN]; B%: 42% -62%, 10.5min. Compound R008-2 was obtained. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.0 Hz, 1H), 7.98 (br s, 1H), 7.81 (dd, J = 2.2, 8.8 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 4.08 (br s, 1H), 3.59 (br s, 1H), 3.49 --3.91 (m, 1H), 3.08 (br dd, J = 6.5, 14.0 Hz, 1H), 2.87 ( s, 3H), 2.41 (br s, 1H), 1.43 (s, 10H), 0.91 (br d, J = 6.6 Hz, 3H).

Step 2: Synthesis of compound R008-3.

Compound R008-2 (0.14 g, 341.21 μmol), compound BB-3 (151 mg, 341.21 μmol), potassium acetate (100 mg, 1.02 mmol) and solvent 1,4- in a pre-dried reaction bottle (10 mL). Dioxane (3 mL) and water (0.3 mL) were added in that order. After replacement with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (24.97 mg, 34.12 μmol) was added, further replaced with nitrogen gas, and heated to 90 ° C. Stirred for 5 hours. After completion of the reaction, the reaction solution was cooled, filtered, washed with methanol (20 mL × 2), and then the filtrate was distilled under reduced pressure to remove the solvent and purified by preparative HPLC. Purification method: Chromatography column: Agela Durashell C18 150 * 25mm 5μm; Mobile phase: [Water (10mM NH4HCO3) -ACN]; B%: 35% -65%, 10.5min. Compound R008-3 was obtained. 1H NMR (400MHz, METHANOL-d4) δ = 8.34 (s, 2H), 8.23 (d, J = 2.1 Hz, 1H), 8.11 (dd, J = 6.0, 8.8 Hz, 1H), 8.05 --7.97 (m, 2H), 7.80 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 2.4, 8.3 Hz, 1H), 7.27 --7.20 (m, 1H), 4.58 (s, 2H), 4.13 (br s, 1H), 3.87 (s, 3H), 3.21 --3.10 (m, 1H), 2.91 (s, 3H), 2.49 (br s, 1H), 1.44 (br s, 9H), 0.97 (br s, 3H).

Step 3: Synthesis of compound R008.

Compound R008-3 (0.14 g, 216.68 μmol) and methylene chloride (3 mL) were added sequentially to a pre-dried reaction bottle (8 mL), and finally 2,6-lutidine (92.87 mg, 866.70 μmol, 100.95 μL). And trimethylsilyltrifluoromethanesulfonate (144.47 mg, 650.03 μmol, 117.46 μL) were added. It was then replaced with nitrogen gas and stirred at 20 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried under reduced pressure and purified by preparative HPLC. Purification method: Chromatography column: Agela Durashell C18 150 * 25mm 5μm; Mobile phase: [Water (10mM NH4HCO3) -ACN]; B%: 15% -45%, 10.5min. Compound R008 was obtained. 1H NMR (400MHz, DMSO-d ₆ ) Shift = 8.35 (s, 1H), 8.14-8.06 (m, 2H), 7.92 (dd, J = 2.1, 8.5 Hz, 1H), 7.77 (br s, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.52 (d, J = 1.9 Hz, 1H), 7.45 (dd, J = 2.4, 8.8 Hz, 1H), 7.30 (dt, J = 2.6, 8.4 Hz, 1H) ), 4.07 --3.86 (m, 2H), 3.78 (s, 3H), 2.94 --2.82 (m, 1H), 2.80 --2.66 (m, 1H), 2.55 (s, 3H), 2.47 --2.31 (m, 2H) ), 1.01 (d, J = 6.8 Hz, 3H).

Control example 6: R009

Step 1: Synthesis of compound R009-2.

Raw material R009-1 (893 mg, 2.25 mmol) and solvent N, N-dimethylformamide (10 mL) were added to a pre-dried 40 mL reaction bottle, and methyl iodide (1.18 g, 8.34 mmol, 519.06 μL) was added. Was added, the reaction system was placed at 0 ° C., then sodium hydride (135.20 mg, 5.63 mmol, 2.5 eq) was added, and the mixture was further stirred at 25 ° C. for 2 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, the organic phase was further extracted with methylene chloride (10 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary-dried under reduced pressure. The mixture was separated by flash column chromatography (petroleum ether: ethyl acetate = 1: 0-3: 1) and purified to obtain the target compound R009-2. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.2 Hz, 1H), 8.00 (s, 6H), 7.81 (dd, J = 2.2, 8.8 Hz, 1H), 7.57 (d, J = 8.6 Hz, 1H), 4.10 (q, J = 7.1 Hz, 2H), 3.69 --3.24 (m, 2H), 3.12 --3.02 (m, 1H), 2.41 (br s, 1H), 2.02 (s, 2H) ), 1.43 (s, 9H), 1.24 (t, J = 7.2 Hz, 2H), 0.91 (br d, J = 6.6 Hz, 3H).

Step 2: Synthesis of compound R009-3.

Add raw material R009-2 (860.00 mg, 2.10 mmol), raw material BB-3 (1.02 g, 2.31 mmol) and solvent water (1 mL), 1,4-dioxane (10 mL) to a pre-dried reaction bottle. Then, potassium acetate (411.40 mg, 4.19 mmol) was added, replaced with nitrogen gas, and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (153.37 mg, 209.60 μmol) was added. It was added, replaced with nitrogen gas, and further stirred at 90 ° C. for 12 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with methylene chloride (10 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then rotary-dried under reduced pressure for flash column chromatography. It was separated by (petroleum ether: ethyl acetate = 1: 0 to 1: 1) and purified to obtain the target compound R009-3. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.35 (d, J = 2.2 Hz, 1H), 8.15 (d, J = 2.2 Hz, 1H), 8.14 --8.10 (m, 1H), 8.03 (br s, 1H), 7.99 (d, J = 2.2 Hz, 1H), 7.87 --7.83 (m, 1H), 7.81 --7.77 (m, 1H), 7.54 (s, 1H), 7.26 (d, J = 2.4 Hz, 1H) ), 7.15 --7.08 (m, 1H), 4.23 --4.04 (m, 1H), 3.98 (s, 3H), 3.65 (br s, 1H), 3.55 --3.27 (m, 1H), 3.13 (br d, J) = 14.3 Hz, 1H), 2.93 (s, 3H), 2.49 (br s, 1H), 2.56 --2.40 (m, 1H), 2.56 --2.40 (m, 1H), 1.47 (s, 10H), 0.96 (br d, J = 6.0 Hz, 3H).

Step 3: Synthesis of compound R009.

Raw material R009-3 (470 mg, 727.41 μmol) and solvent methylene chloride (5 mL) were added to a pre-dried reaction bottle, followed by R009-4 (311.78 mg, 2.91 mmol, 338.89 μL), trimethylsilyltrifluoromethane. Ssulfonate (485.02 mg, 2.18 mmol, 394.32 μL) was added and further stirred at 25 ° C. for 12 hours. After completion of the reaction, the reaction solution was directly spin-dried under reduced pressure and preparative HPLC (chromatography column: Agela Durashell C18 150 * 25mm 5 μm; mobile phase: [water (10 mM NH4HCO3) -ACN]; B%: 15% Separation by -45%, 10.5 min) gave product R009. ^{1 1} H NMR and MS detection show that the structure is correct, HPLC detection shows that the retention time is 1.698 minutes, SFC detection shows that the product has a single arrangement. It was shown that ee% = 100%. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.17 --8.13 (m, 1H), 8.13 --8.10 (m, 2H), 7.94 (d, J = 2.2 Hz) , 1H), 7.86 --7.82 (m, 1H), 7.79 --7.75 (m, 1H), 7.26 --7.23 (m, 1H), 7.12 (ddd, J = 2.4, 7.5, 8.8 Hz, 1H), 4.13 --4.05 (m, 1H), 4.02 --3.95 (m, 4H), 2.88 (br s, 5H), 2.60 --2.55 (m, 2H), 2.49 (s, 3H), 2.35 (qd, J = 6.5, 13.0 Hz, 1H), 1.04 (d, J = 6.8 Hz, 3H), 1.07 --1.00 (m, 1H), 1.07 --1.00 (m, 1H), 1.07 --1.00 (m, 1H).

Control example 7: R010

Step 1: Synthesis of compound R010-2 Compound R010-1 (0.301 g, 1.29 mmol), compound BB-1 (0.2 g, 647.26 μmol), cesium carbonate (0.843 g, 2.59 mmol) in N, N-dimethylformamide ( It was dissolved in 5.00 mL) and stirred at 60 ° C. for 2 hours. After completion of the reaction, the reaction solution was spin-dried, diluted with water (50 mL), extracted with methylene chloride (50 mL), and the organic phase was spin-dried to obtain the target compound R010-2.

Step 2: Synthesis of Compound R010 Compound R010-2 (0.2 g, 514.04 μmol), Compound BB-8 (0.177 g, 513.71 μmol), Potassium Acetate (0.202 g, 2.06 mmol), Phaleosene Palladium Chloride (0.038 g, 51.93 μmol) ) Was dissolved in dioxane (5.00 mL) and water (1 mL), and the reaction solution was stirred at 100 ° C. for 1 hour under the protection of nitrogen gas. After completion of the reaction, the reaction solution was spin-dried, diluted with water (50 mL), extracted with methylene chloride (50 mL), and the organic phase was spin-dried. Preparative HPLC of the resulting material (separation method: chromatography column: Phenomenex Gemini C18 250 * 50mm 10 μm; mobile phase: [water (0.05% ammonium hydroxide v / v) -ACN]; B%: 23% -33 Separation was performed by%, 8min)) to obtain the target compound R010. ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.57 (d, J = 2.5 Hz, 1 H), 8.31 --8.38 (m, 2 H), 8.09 (dd, J = 8.8, 5.8 Hz, 1 H) ), 8.02 (dd, J = 8.5, 2.0 Hz, 1 H), 7.88 (d, J = 2.0 Hz, 1 H), 7.80 (d, J = 8.5 Hz, 1 H), 7.53 (dd, J = 8.5) , 2.5 Hz, 1 H), 7.22 --7.30 (m, 1 H), 4.26 (t, J = 6.3 Hz, 2 H), 2.85 (t, J = 6.5 Hz, 2 H), 2.51 (s, 3 H) ), 2.43 (s, 6 H).

Control example 8: R011

Step 1: Synthesis of compound R011-3 Compound R011-1 (1 g, 4.63 mmol) was dissolved in methylene chloride (10 mL), and compound R011-2 (428.45 mg, 4.86 mmol, 530.92 μL), EDCI ( 905.12 mg, 4.72 mmol, 1.02 eq), HOPO (601.70 mg, 5.42 mmol, 1.17 eq) and triethylamine (1.87 g, 18.52 mmol, 2.58 mL, 4 eq) were added and the reaction was added under 40 ° C. conditions 16 Stirred for hours. After completion of the reaction, the reaction solution was washed with 10 mL of water, and the organic phase was rotationally dried to obtain the target compound R011-3. ^{1 1} HNMR (400 MHz, CHLOROFORM-d) δ = 7.40 (d, J = 2.0 Hz, 1 H), 7.15 --7.24 (m, 1 H), 6.71 (br s, 1 H), 6.49 (d, J = 8.5 Hz, 1 H), 5.49 (br s, 2 H), 3.39 (q, J = 5.4 Hz, 2 H), 2.43 (t, J = 5.9 Hz, 2 H), 2.19 (s, 6 H).

Step 2: Synthesis of Compound R011-4 Compound R011-3 (1.1 g, 3.84 mmol) was dissolved in formic acid (22.67 g, 492.48 mmol, 18.58 mL), and the reaction mixture was stirred under the condition of 100 ° C. for 16 hours. After completion of the reaction, the reaction solution was spin-dried to obtain the target compound R011-4. MS-ESI m / z: 297.9 [M + H] ⁺ .

Step 3: Synthesis of compound R011-7 Compound R011-5 (0.2 g, 799.67 μmol) is dissolved in pyridine (3 mL), compound R011-6 (158.74 mg, 815.67 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried to obtain the target compound R011-7. ^{1 1} HNMR (400 MHz, CHLOROFORM-d) δ = 8.25 (br t, J = 7.8 Hz, 2 H), 8.17 (d, J = 1.5 Hz, 1 H), 8.01 (d, J = 1.3 Hz, 1 H) ), 7.67 --7.75 (m, 2 H), 6.83 (br s, 1 H), 3.71 (s, 3 H), 1.26 (s, 12 H).

Step 4: Synthesis of Compound R011 Compound R011-7 (0.3 g, 734.84 μmol) was dissolved in dioxane (5 mL) and water (1 mL), and potassium acetate (288.48 mg, 2.94 mmol) and compound R011-4 were dissolved therein. (217.63 mg, 734.84 μmol) and Pd (dppf) Cl2 (120.02 mg, 146.97 μmol) were added, and the reaction solution was stirred under the condition of 100 ° C. for 3 hours under the protection of nitrogen gas. After completion of the reaction, the reaction solution was spin-dried and separated by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound R011. ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.37 (s, 1 H), 8.35 (s, 1 H), 8.27 (d, J = 2.3 Hz, 1 H), 8.15 (s, 1 H), 8.08 (dd, J = 8.5, 2.3 Hz, 1 H), 7.92 (d, J = 2.3 Hz, 1 H), 7.83 (dd, J = 8.8, 5.3 Hz, 2 H), 7.78 (d, J = 8.5) Hz, 1 H), 7.42 (t, J = 8.8 Hz, 2 H), 4.12 (br t, J = 5.9 Hz, 2 H), 3.69 (s, 3 H), 2.63 (br t, J = 6.0 Hz) , 2 H), 2.24 (s, 6 H). MS-ESI m / z: 498.3 [M + H] ⁺ .

Control example 9: R012

Step 1: Synthesis of compound R012-1
2-Methoxy-3-amino-5-pyridinebolate (0.5 g, 2.00 mmol) is dissolved in pyridine (2.0 mL) and 2,4-difluorobenzenesulfonyl chloride (446.28 mg, 2.10 mmol) is added at 25 ° C. , The reaction solution was stirred at 28 ° C. for 16 hours, and the reaction was completed. Rotately dry the organic solvent, add water (200 mL), wash 3 times with methylene chloride (100 mL), combine the organic phases, dry over anhydrous sodium sulfate, spin dry the organic phase to the compound of interest. Obtained R012-1. ¹ H NMR (400MHz, Methanol-d4) δ: 8.64 (d, J = 4.5 Hz, 1H), 8.22 (d, J = 1.8 Hz, 1H), 7.94 (d, J = 1.8 Hz, 1H), 7.84- 7.70 (m, 1H), 7.62 (dd, J = 6.0, 7.8 Hz, 1H), 7.11 --6.96 (m, 1H), 3.77 (s, 3H), 1.36 (s, 12H).

Step 2: Synthesis of Compound R012-3 Compound 2-amino-5-bromobenzoic acid (2.0 g, 9.26 mmol) was dissolved in DMF (20.0 mL) and triethylamine (1.87 g, 18.52 mmol) and HATU (3.52 g, 9.26 mmol) and R012-2 (1.08 g, 9.26 mmol) were added, and the mixture was stirred at 28 ° C. for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, the mixture was poured into water (200 mL), and the mixture was extracted 3 times with methylene chloride (100 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure to obtain the target compound R012-3. ¹ H NMR (400MHz, Methanol-d4) δ: 7.60 (d, J = 2.3 Hz, 1H), 7.27 (dd, J = 2.4, 8.7 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 3.47 (t, J = 7.0 Hz, 2H), 2.80 --2.62 (m, 6H), 1.13 (t, J = 7.3 Hz, 6H).

Step 3: Synthesis of Compound R012-4 Compound R012-3 (1.0 g, 3.18 mmol) is dissolved in ethanol (40 mL), formamidine acetate (662.64 mg, 6.36 mmol) is added, and the temperature is 80 ° C. for 2 hours. Stirred. After completion of the reaction, the solvent was removed under reduced pressure, the mixture was poured into water (10 mL), and the mixture was extracted 3 times with methylene chloride (10 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure to obtain the target compound R012-4. ¹ H NMR (400MHz, Methanol-d4) δ: 8.35 (d, J = 2.3 Hz, 1H), 8.30 (s, 1H), 7.94 (dd, J = 2.3, 8.8 Hz, 1H), 7.62 (d, J) = 8.5 Hz, 1H), 4.15 (t, J = 6.3 Hz, 2H), 2.88 (t, J = 6.4 Hz, 2H), 2.68 (q, J = 7.0 Hz, 4H), 1.01 (t, J = 7.2) Hz, 6H).

Step 4: Synthesis of compound R012
R012-4 (0.2 g, 616.87 μmol) and R012-1 (262.94 mg, 616.87 μmol) were dissolved in dioxane (5.00 mL) and water (1.00 mL), and [1,1'-bis (diphenylphosphino) was dissolved therein. ) Ferrocene] Dichloropalladium (II) (100.75 mg, 123.37 μmol) and potassium acetate (242.17 mg, 2.47 mmol) were added, and the reaction solution was stirred at 95 ° C. for 2 hours under nitrogen gas protection. Water (50 mL) was added to the mixture, extracted 3 times with methylene chloride (10 mL), dried over anhydrous sodium sulfate, the organic phase was rotationally dried, and the resulting oily residue was subjected to thick preparative thin layer chromatography. Separation was performed by (eluent: methylene chloride / methanol = 15: 1), and further separation was performed by an HPLC preparative column to obtain the target compound R012. ^{1 1} H NMR (400MHz, CDCl ₃ ) δ: 8.31 (br s, 1H), 8.14 --7.90 (m, 3H), 7.89 --7.62 (m, 3H), 7.01 --6.78 (m, 2H), 3.97 (br s) , 2H), 3.89 (s, 3H), 2.71 (br s, 2H), 2.48 (q, J = 6.5 Hz, 4H), 0.87 (br t, J = 6.9 Hz, 6H). MS-ESI m / z: 544.2 [M + H] ⁺ , 546.2 [M + H + 2] ⁺ .

Example 1: WX001

Step 1: Synthesis of compound WX001-3
WX001-1 (500.00 mg, 2.31 mmol), WX001-2 (350.00 mg, 2.28 mmol, 1.0HCl), triethylamine (730.00 mg, 7.21 mmol, 1.00 mL), 2-hydroxypyridine N-oxide (260.00 mg, 2.34 mmol) ) And 1- (3-Dimethylaminopropyl) -3-acetaldehyde hydrochloride (450.00 mg, 2.35 mmol) were dissolved in methylene chloride (50.00 mL) and reacted at 50 ° C. for 16 hours. After completion of the reaction, the mixture was washed with water (50 mL), the organic phase was concentrated to obtain the target compound WX001-3, which was used as it was in the next step. MS-ESI m / z: 315.0 [M + H] ⁺ , 317.0 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX001-4 A formic acid solution (20 mL) of compound WX001-3 (900.00 mg, 2.52 mmol) was stirred and reacted at 100 ° C. for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound WX001-4, which was used as it was in the next step. ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ: 8.36 (d, J = 2.26 Hz, 1 H) 8.13 --8.24 (m, 1 H) 7.73 --7.82 (m, 1 H) 7.49 --7.58 (m, 1) H) 4.19 (t, J = 6.02 Hz, 2 H) 4.07 (q, J = 7.03 Hz, 2 H) 2.82 (t, J = 6.02 Hz, 2 H) 1.09 --1.20 (m, 3 H). MS-ESI m / z: 324.9 [M + H] ⁺ , 326.9 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX001-5
Ammonia was introduced into a solution of WX001-4 (950.00 mg, 2.92 mmol) in methanol (30 mL) at 0 ° C. for 0.5 hours. After that, the mixture was stirred at 60 ° C. for 16 hours in a packed kettle to react. After completion of the reaction, the mixture was cooled to room temperature and concentrated under reduced pressure to obtain WX001-5, which was used as it was in the next step. MS-ESI m / z: 296.0 [M + H] ⁺ , 298.0 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX001
WX001-5 (200.00 mg, 675.40 μmol), BB-3 (300.00 mg, 648.38 μmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (55.00 mg, 75.17 μmol) and acetate A mixed solution of potassium (300.00 mg, 3.06 mmol) dioxane (10 mL) and water (2 mL) was stirred and reacted at 100 ° C. for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was washed with water (30 mL) and extracted with methylene chloride (30 mL × 2). The organic phase was distilled under reduced pressure, and the obtained residue was separated by a chromatography column (eluent: methylene chloride / methanol = 0% -5%) to obtain the target compound WX001. ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ: 8.34 (d, J = 2.26 Hz, 1 H) 8.28 (s, 1 H) 8.11 --8.21 (m, 2 H) 7.99 (d, J = 2.26 Hz, 1 H) 7.77 --7.91 (m, 2 H) 7.56 (s, 1 H) 7.27 (d, J = 2.51 Hz, 1 H) 7.09 --7.18 (m, 1 H) 5.33 --5.63 (m, 2 H) 4.35 (t, J = 6.02 Hz, 2 H) 4.00 (s, 3 H) 2.86 (t, J = 6.02 Hz, 2 H). MS-ESI m / z: 532.1 [M + H] ⁺ .

Example 2: WX002

Step 1: Synthesis of compound WX002-1 Compound R001-1 (200.00 mg, 589.66 μmol), BB-4 (203.17 mg, 589.66 μmol), potassium acetate (231.48 mg, 2.36 mmol) was added to dioxane (1 mL) and water (1 mL). It was dissolved in 1 mL), after which ferrocene dichloride palladium (8.63 mg, 11.79 μmol) was added, and the mixture was heated to 100 ° C. under the protection of nitrogen gas and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (10 mL), and extracted with methylene chloride (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / = 1:10), and then further separated by an HPLC preparative column. The target compound WX002-1 was obtained. ¹ H NMR (400MHz, Methanol-d ₄ ) δ: 8.61 (d, J = 2.3 Hz, 1H), 8.41 --8.30 (m, 2H), 8.09 (dd, J = 5.8, 9.0 Hz, 1H), 8.02 ( dd, J = 2.0, 8.5 Hz, 1H), 7.89 (d, J = 2.3 Hz, 1H), 7.85 --7.76 (m, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.55 (dd, J = 2.5, 8.5 Hz, 1H), 7.30 --7.17 (m, 1H), 4.20 --4.14 (m, 2H), 4.22 --4.00 (m, 2H), 2.58 --2.41 (m, 5H), 2.30 --2.03 (m) , 2H), 1.23 (t, J = 7.0 Hz, 3H). MS-ESI m / z: 558.09 [M + H] ⁺ , 560.9 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX002 Compound WX002-1 (200.00 mg, 357.78 μmol) was dissolved in a methylamine alcohol solution (20 mL), heated to 80 ° C., and stirred for 2 hours for reaction. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15), and further separated by an HPLC preparative column. The target compound WX002 was obtained. ¹ H NMR (400MHz, Methanol-d ₄ ) δ: 8.59 (s, 1H), 8.42 --8.30 (m, 2H), 8.09 (dd, J = 5.8, 8.8 Hz, 1H), 8.03 (br d, J = 8.5 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.81 (br d, J = 8.8 Hz, 1H), 7.54 (dd, J = 2.5, 8.5 Hz, 1H), 7.36 --7.16 (m) , 1H), 4.15 (t, J = 6.9 Hz, 2H), 2.68 (s, 3H), 2.50 (s, 3H), 2.39 --2.24 (m, 2H), 2.14 (quin, J = 7.0 Hz, 2H) . MS-ESI m / z: 543.9 [M + H] +, 545.9 [M + H + 2] +.

Example 3: WX003

Step 1: Synthesis of Compound WX003-1 Compound R001 (800.00 mg, 1.39 mmol) was dissolved in tetrahydrofuran (10.0 mL) and water (10.0 mL), followed by the addition of lithium hydroxide (233.51 mg, 5.57 mmol). The reaction solution was stirred at 10 ° C. for 1 hour to react. After completion of the reaction, the reaction solution was extracted with methylene chloride (10 mL × 3), the aqueous phase was adjusted to PH about 2 with dilute hydrochloric acid (1 M) at 0 ° C., and extracted with methylene chloride (100 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX003-1. MS-ESI m / z: 547.0 [M + H] ⁺ , 549.0 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX003-2 Compound WX003-1 (200.00 mg, 365.66 μmol) was dissolved in thionyl chloride (5.0 mL), heated to 80 ° C., and allowed to flow for 1 hour. After completion of the reaction, the solvent was removed under reduced pressure to obtain the target compound WX003-2, which was used as it was in the next step.

Step 3: Synthesis of compound WX003 WX003-2 (100.00 mg) was dissolved in anhydrous methylene chloride (5 mL) of compound isopropylamine (12.55 mg, 212.24 μmol) and triethylamine (35.79 mg, 353.74 μmol) and stirred at 0 ° C. , 176.87 μmol) of methylene chloride (1 mL) solution was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour for reaction. After completion of the reaction, the solvent was removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15), and further separated by an HPLC preparative column (Phenomenex Gemini C18 250 * 50 mm). * 10 μm; Mobile phase: [Water (0.04% NH ₃ H ₂ O) -ACN]; B%: 10% -40%, 40 min) to obtain the target compound WX003. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.37 (d, J = 1.8 Hz, 1H), 8.25 --8.07 (m, 3H), 8.00 (d, J = 2.3 Hz, 1H), 7.92 --7.73 (m, 2H), 7.55 (s, 1H), 7.30 (br s, 1H), 7.18 --7.01 (m, 1H), 5.73 --5.59 (m, 1H), 4.19 --4.05 (m, 3H), 4.00 (s, 3H) ), 2.34 --2.13 (m, 4H), 1.19 (d, J = 6.5 Hz, 6H). MS-ESI m / z: 588.1 [M + H] +, 560.1 [M + H + 2] +.

Example 4: WX004

Step 1: Synthesis of compound WX004-1 Compound WX002-1 (0.3 g, 536.66 μmol) is dissolved in tetrahydrofuran (10 mL) and water (10 mL), followed by the addition of lithium hydroxide (90.08 mg, 2.15 mmol). Then, the reaction solution was stirred at 15 ° C. for 2 hours. After completion of the reaction, the reaction solution was extracted with methylene chloride (10 mL × 3), the aqueous phase was adjusted to PH ~ 2 with dilute hydrochloric acid (1 M) at 0 ° C., and extracted with methylene chloride (10 mL × 3), 3 The organic phases obtained from each extraction were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX004-1, which was used as it was in the next step. MS-ESI m / z: 531.0 [M + H] ⁺ , 532.0 [M + H + 2] ⁺ .

Step 2: Synthesis of Compound WX004 Compound WX004-1 (50 mg, 94.17 μmol) was dissolved in methylene chloride (3 mL), TEA (19.06 mg, 188.34 μmol) and HATU (35.81 mg, 94.17 μmol), isopropylamine (6.12). mg, 103.59 μmol) was added and stirred at 10 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with methylene chloride (10 mL × 3). Organic obtained by 3 extractions. The phases were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure and a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15). ), And further separated by an HPLC preparative column to obtain the target compound WX004. ¹ H NMR (400 MHz, Methanol-d ₄ ) δ: 8.57 (d, J = 2.0 Hz, 1H), 8.44 --8.30 ( m, 2H), 8.09 (dd, J = 5.8, 8.8 Hz, 1H), 8.02 (dd, J = 2.3, 8.5 Hz, 1H), 7.89 (d, J = 2.0 Hz, 1H), 7.81 (d, J = 8.5 Hz, 1H), 7.53 (dd, J = 2.5, 8.3 Hz, 1H), 7.41 --7.07 (m, 1H), 4.15 (t, J = 7.0 Hz, 1H), 4.23 --4.09 (m, 1H) , 3.97 --3.83 (m, 1H), 2.51 (s, 3H), 2.34 --2.23 (m, 2H), 2.17 --2.03 (m, 2H), 1.12 (d, J = 6.5 Hz, 6H). MS-ESI m / z: 572.0 [M + H] ⁺ , 574.0 [M + H + 2] ⁺ .

Example 5: WX005

Step 1: Synthesis of Compound WX005 Compound WX004-1 (50 mg, 94.17 μmol) was dissolved in methylene chloride (3 mL), TEA (19.06 mg, 188.34 μmol) and HATU (35.81 mg, 94.17 μmol), tetrahydropyrrole (7.37). mg, 103.59 μmol) was added, and the mixture was stirred at 10 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with methylene chloride (10 mL × 3). Organic obtained by 3 extractions. The phases were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure and a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15). ), And further separated by an HPLC preparative column to obtain the target compound WX005. ¹ H NMR (400MHz, 400MHz, Methanol-d ₄ ) δ: 8.58 (s, 1H), 8.40 --8.26 (m, 2H) ), 8.09 (dd, J = 5.9, 8.9 Hz, 1H), 8.02 (br d, J = 8.5 Hz, 1H), 7.89 (s, 1H), 7.79 (dd, J = 3.5, 8.3 Hz, 1H), 7.54 (dd, J = 2.5, 8.5 Hz, 1H), 7.41 --7.18 (m, 1H), 4.18 (br t, J = 6.8 Hz, 2H), 3.49 (t, J = 6.8 Hz, 2H), 3.30- 3.23 (m, 2H), 3.30 --3.22 (m, 2H), 2.50 (m, 5H), 2.17 (quin, J = 6.8 Hz, 2H), 1.96 (quin, J = 6.8 Hz, 2H), 1.82 (quin) , J = 6.8 Hz, 2H). MS-ESI m / z: 583.9 [M + H] ⁺ , 586.0 [M + H + 2] ⁺ .

Example 6: WX006

Step 1: Synthesis of Compound WX006-1 Compound R001-1 (500 mg, 1.53 mmol), BB-5 (518.33 mg, 1.53 mmol), potassium acetate (599.90 mg, 6.11 mmol) in dioxane (5 mL) and water (5 mL) It was dissolved in 1 mL), after which ferrocene dichloride palladium (249.59 mg, 305.63 μmol) was added, and the mixture was heated to 100 ° C. under the protection of nitrogen gas and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (100 mL), and extracted with methylene chloride (100 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent is removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / = 1:10), and further separated by an HPLC preparative column. The target compound WX006-1 was obtained. MS-ESI m / z: 542.1 [M + H] ⁺ , 544.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX006-2 Compound WX006-1 (0.3 g, 553.87 μmol) is dissolved in tetrahydrofuran (10.0 mL) and water (10.0 mL), followed by the addition of lithium hydroxide (92.97 mg, 2.22 mmol). Then, the reaction was stirred at 15 ° C. for 2 hours. After completion of the reaction, the reaction solution was extracted with methylene chloride (10 mL × 3), the aqueous phase was adjusted to PH ~ 2 with dilute hydrochloric acid (1 M) at 0 ° C, extracted with methylene chloride (10 mL × 3), and water. The phases were collected and the solvent was removed under reduced pressure. Further, methanol (60 mL) was added, filtered, and the mother liquor was concentrated under reduced pressure to obtain the target compound WX006-2, which was used as it was in the next step. MS-ESI m / z: 515.0 [M + H] ⁺ , 515.8 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX006 Compound WX006-2 (0.12 g, 233.65 μmol) was dissolved in DMF (3 mL), DIEA (60.40 mg, 467.30 μmol) and HATU (88.84 mg, 233.65 μmol), isopropylamine (13.81). mg, 233.65 μmol) was added, and the mixture was stirred at 10 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with methylene chloride (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent is removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1:15), and further separated by an HPLC preparative column for the purpose. Compound WX006 was obtained. ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ: 8.62 (d, J = 2.0 Hz, 1H), 8.39 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.98 --7.83 (m, 2H) , 7.81 --7.69 (m, 1H), 5.54 (br s, 1H), 5.35 --5.13 (m, 1H), 4.16 --4.03 (m, 2H), 2.60 (s, 3H), 2.37 (d, J = 7.0) Hz, 6H), 2.22 --2.00 (m, 1H), 2.22 --2.00 (m, 4H), 1.10 (d, J = 6.5 Hz, 6H). MS-ESI m / z: 555.2 [M + H] ⁺ , 557.0 [M + H + 2] ⁺ .

Example 7: WX007

Step 1: Synthesis of compound WX007 Compound WX006-2 (50 mg, 94.17 μm) is dissolved in methylene chloride (3 mL), DIEA (60.39 mg, 467.30 μmol) and HATU (88.84 mg, 233.65 μmol), tetrahydropyrrole ( 16.62 mg (233.65 μmol) was added, and the mixture was stirred at 10 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with methylene chloride (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent is removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / = 1: 15), and further separated by an HPLC preparative column. The target compound WX007 was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.62 (d, J = 2.0 Hz, 1H), 8.38 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 7.91 (d, J = 2.0 Hz) , 1H), 7.85 (dd, J = 2.1, 8.4 Hz, 1H), 7.76 (d, J = 8.3 Hz, 1H), 5.28 (br s, 1H), 4.11 (t, J = 7.2 Hz, 2H), 3.46 --3.27 (m, 4H), 2.61 (s, 3H), 2.45 --2.27 (m, 8H), 2.19 --2.05 (m, 2H), 1.89 (td, J = 7.1, 13.7 Hz, 2H), 1.82 - 1.74 (m, 2H). MS-ESI m / z: 567.2 [M + H] ⁺ , 568.1 [M + H + 2] ⁺ .

Example 8: WX008, WX009

Step 1: Synthesis of compound WX008-2 Compound WX008-1 (2.00 g, 15.61 mmol) is dissolved in methanol (5 mL), and then sodium boron hydride (590.49 mg, 15.61 mmol) is added at 0 ° C. to 0. The mixture was stirred at ° C. for 2 hours and reacted. After completion of the reaction, the mixture was cooled to room temperature, saturated NH ₄ Cl (5 mL) solution was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX008-2. ^{1 1} H NMR (400MHz, Methanol-d ₄ ) δ: 4.14 --4.11 (m, 1H), 3.69 --3.65 (s, 3H), 2.70 --2.57 (m, 1H), 2.55 --2.43 (m, 2H), 2.16 --2.07 (m, 2H).

Step 2: Synthesis of Compound WX008-3 Compound WX008-2 (500.00 mg, 3.84 mmol) and triethylamine (777.14 mg, 7.68 mmol) are dissolved in methylene chloride (5 mL), followed by methanesulfonyl chloride (1.72 g) at 0 ° C. , 14.98 mmol) was added, and the mixture was stirred and reacted at 0 ° C. for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, water (5 mL) was added to quench the reaction, and the mixture was extracted with ethyl acetate (15 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX008-3. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ: 5.03 --4.90 (m, 1H), 4.85 (br s, 2H), 3.72 --3.69 (s, 3H), 3.08 (s, 3H), 2.91 --2.79 ( m, 1H), 2.76 --2.66 (m, 2H), 2.55 --2.42 (m, 2H).

Step 3: Synthesis of Compound WX008-4 Compound BB-1 (600.00 mg, 2.67 mmol), WX008-3 (555.18 mg, 2.67 mmol) and cesium carbonate (1.74 g, 5.33 mmol) in N, N-dimethylformamide methyl acetal. It was dissolved in (5 mL), heated to 60 ° C., and stirred for 6 hours. After completion of the reaction, the mixture was cooled to room temperature, and after completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (100 mL), and extracted with ethyl acetate (50 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure and separated by a preparative chromatography plate (eluent: petroleum ether / ethyl acetate = 3: 1) to obtain the target compound WX008-4. MS-ESI m / z: 337.0 [M + H] ⁺ , 339.0 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX008-5
BB-6 (0.2 g, 290.06 μmol, purity: 59.85%), WX008-4 (0.177 g, 289.99 μmol), potassium acetate (0.114 g, 1.16 mmol) and [1,1'-bis (diphenylphosphino) ferrocene ] A suspension of dichloropalladium (II) (0.021 g, 28.70 μmol) dioxane (8 mL) and water (1.6 mL) was replaced with nitrogen gas three times, followed by 100 reaction solutions under nitrogen gas protection. The mixture was heated to ° C. and stirred for 60 minutes. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurried with water (50 mL), washed and then extracted with methylene chloride (50 mL). The organic phase was spin-dried and separated by column chromatography (MeOH: DCM = 0% -10%) to give WX008-5. MS-ESI m / z: 542.9 [M + H] ⁺ .

Step 5: Synthesis of compound WX008-6
A suspension of WX008-5 (0.25 g) in methylamine (10 mL) was stirred at 80 ° C. for 16 hours. After completion of the reaction, the reaction solution was concentrated and spin-dried. Separation was performed by preparative thin layer chromatography (DCM: MeOH = 10: 1) to obtain the target compound WX008-6.

Step 6: Synthesis of compounds WX008 and WX009
WX008-6 was separated by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: 40% -40%) and cis-trans isomers. WX008 (Rt = 4.034 min) and WX009 (Rt = 4.829 min) were obtained. According to NOE identification, WX008 is a cis isomer: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.42 (d, J = 1.25 Hz, 1 H) 8.34 (s, 1 H) 8.23 (d) , J = 2.01 Hz, 1 H) 8.10 --8.18 (m, 2 H) 7.86 (dd, J = 8.53, 2.26 Hz, 1 H) 7.75 (t, J = 2.26 Hz, 1 H) 7.63 (d, J = 8.53 Hz, 1 H) 7.33 (dd, J = 8.53, 2.51 Hz, 1 H) 7.18 (ddd, J = 8.91, 7.91, 2.51 Hz, 1 H) 4.82 --4.98 (m, 1 H) 2.82 --2.95 (m) , 1 H) 2.63 --2.74 (m, 5 H) 2.48 --2.60 (m, 2 H), MS-ESI m / z: 542.0 [M + H] ⁺ . WX009 is a trans isomer: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.44 (br s, 1 H) 8.29 (s, 1 H) 8.18 --8.26 (m, 2 H) 8.15 (dd, dd, J = 8.91, 5.90 Hz, 1 H) 7.90 (br d, J = 8.53 Hz, 1 H) 7.77 (s, 1 H) 7.66 (d, J = 8.53 Hz, 1 H) 7.28 --7.41 (m, 1 H) ) 7.19 (br t, J = 8.28 Hz, 1 H) 5.22 (quin, J = 8.60 Hz, 1 H) 3.00 --3.11 (m, 1 H) 2.73 --2.86 (m, 2 H) 2.57 --2.70 (m,) 5 H), MS-ESI m / z: 542.0 [M + H] ⁺ .

Example 9: WX010, WX011

Step 1: Synthesis of compound WX010-1
BB-9 (0.28 g, 381.85 μmol, purity: 53.91%), WX008-4 (0.233 g, 381.74 μmol, purity: 55.24%), potassium acetate (0.15 g, 1.53 mmol) and [1,1'-bis (1,1'-bis) Diphenylphosphino) ferrocene] A suspension of dioxane (8 mL) and water (1.6 mL) of dichloropalladium (II) (0.028 g, 38.27 μmol) was replaced with nitrogen gas three times, followed by nitrogen gas protection. , The reaction solution was stirred at 100 ° C. for 60 minutes. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurried with water (100 mL), washed, and then extracted with methylene chloride (100 mL). The organic phase was spin-dried and separated by column chromatography (MeOH: DCM = 0% -10%) to give WX010-1. MS-ESI m / z: 526.0 [M + H] ⁺ .

Step 2: Synthesis of compound WX010-2
A suspension of WX010-1 (0.15 g, 158.31 μmol) in methylamine (10 mL) was stirred at 80 ° C. for 16 hours. After completion of the reaction, the reaction solution was concentrated and spin-dried. Separation was performed by preparative thin layer chromatography ((DCM: MeOH = 10: 1)) to obtain the target compound WX010-2.

Step 3: Synthesis of compounds WX010 and WX011
WX010-2 was separated by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: 40% -40%), and the target compound WX010 (Rt = 3.703 min) and WX011 (Rt = 4.458 min) were obtained. According to NOE identification, WX010 is a cis isomer: ¹ H NMR (400 MHz, METHANOL-d4) δ: 8.33 (s, 1 H) 8.20 --8.29 (m, 2 H) 8.14 (d, J = 1.76) Hz, 1 H) 7.92 (dd, J = 8.41, 2.13 Hz, 1 H) 7.71 (t, J = 2.13 Hz, 1 H) 7.67 (d, J = 8.53 Hz, 1 H) 4.83 --4.97 (m, 1) H) 2.82 --2.96 (m, 1 H) 2.62 --2.72 (m, 5 H) 2.53 --2.61 (m, 2 H) 2.51 (s, 3 H) 2.40 (s, 3 H), MS-ESI m / z : 525.1 [M + H] ⁺ . WX011 is a trans isomer: ¹ H NMR (400 MHz, METHANOL-d4) δ: 8.52 (s, 1 H) 8.19 --8.35 (m, 3 H) 7.93 (dd, J = 8.53, 2.26 Hz, 1 H ) 7.90 --7.99 (m, 1 H) 7.79 (t, J = 2.01 Hz, 1 H) 7.66 (d, J = 8.53 Hz, 1 H) 5.21 (quin, J = 8.60 Hz, 1 H) 3.00 --3.12 ( m, 1 H) 2.74 --2.86 (m, 2 H) 2.59 --2.72 (m, 4 H) 2.59 --2.72 (m, 1 H) 2.52 (s, 3 H) 2.37 (s, 3 H), MS-ESI m / z: 525.1 [M + H] ⁺ .

Example 10: WX012, WX013

Step 1: Synthesis of compound WX012-1 Compound WX008-4 (150.00 mg, 444.88 μmol), BB-4 (189.83 mg, 444.88 μmol), potassium acetate (174.64 mg, 1.78 mmol) was added to dioxane (5 mL) and water (5 mL). It was dissolved in 1 mL), after which Pd (dppf) Cl ₂ (65.10 mg, 88.98 μmol) was added, heated to 95 ° C. under the protection of nitrogen gas, and stirred for 3 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (10 mL), and extracted with methylene chloride (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure and separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 10: 0.01) to obtain the target compound WX012-1. Obtained. MS-ESI m / z: 556.9 [M + H] ⁺ , 558.9 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX012-2
WX012-1 (200.00 mg, 359.07 μmol) was dissolved in a methylamine alcohol solution (20 mL), heated to 80 ° C. and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15), and further separated by an HPLC preparative column (water s). Xbridge 150 * 25mm 5μμm; Mobile phase: [Water (10mM NH ₄ HCO ₃ ) -ACN]; B%: 5% -35%, 10min) Separation to give compound WX012-2.

Step 3: Synthesis of WX012 and WX013
WX012-2 was separated by supercritical fluid chromatography (separation condition column: OJ (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: 35% -35%). The cis-trans isomers WX012 and WX013 were obtained, the retention times were 1.447 min and 1.686 min, and the proportion was 1: 1. According to NOE identification, WX012 is a cis isomer product: ^{1 1} H NMR (400 MHz, CDCl ₃ )) δ: 8.50 (d, J = 2.0 Hz, 1H), 8.36 --8.17 (m, 2H), 8.03 (dd, J = 5.8, 8.8 Hz, 1H), 7.87 --7.66 (m, 3H), 7.24 (dd, J = 2.4, 7.9 Hz, 1H), 7.12 --6.96 (m, 1H), 5.73 (br s, 1H), 5.15 --4.93 (m, 1H), 2.83 --2.62 (m, 8H), 2.47 (s, 3H). MS-ESI m / z: 555.9 [M + H] ⁺ , 557.9 [M + H + 2] ⁺ . WX013 is a Lance isomer product: ^{1 1} H NMR (400 MHz, CDCl ₃ ) δ: 8.51 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 2.0 Hz, 1H), 8.10 --7.88 (m) , 2H), 7.91 --7.52 (m, 3H), 7.37 --7.23 (m, 1H), 7.11 --6.88 (m, 1H), 5.48 (br s, 1H), 5.14 (quin, J = 8.4 Hz, 1H) , 3.11 --2.95 (m, 1H), 2.93 --2.67 (m, 7H), 2.47 (s, 3H). MS-ESI m / z: 555.9 [M + H] ⁺ , 557.9 [M + H + 2] ⁺ .

Example 11: WX014, WX015

Step 1: Synthesis of Compound WX014-1 Compound WX008-4 (0.5 g, 1.48 mmol), lithium hydroxide monohydrate (124.45 mg, 2.97 mmol) in methanol (4.00 mL), tetrahydrofuran (4 ml) and water (4 mL) ), And further stirred at 20 ° C. for 12 hours. The reaction mixture was spin-dried, diluted with water (20 mL), adjusted to pH = 4 with hydrochloric acid (2 mol / L), extracted with ethyl acetate (20 mL × 3), and the organic phase was spin-dried to the target compound WX014. I got -1.

Step 2: Synthesis of compound WX014-2 Compound WX014-1 (0.22 g, 680.82 μmol) is dissolved in N, N-dimethylformamide (5 mL) and further dissolved in N, N-diisopropylethylamine (5 mL) at 0 ° C. under nitrogen gas protection. 351.95 mg, 2.72 mmol), isopropylamine (120.73 mg, 2.04 mmol, 175.48 μL) and 2- (7-benzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (388.30 mg, 1.02 mmol) Was added and the mixture was stirred at 20 ° C. for 12 hours. Water (20 mL) was added to the reaction mixture, the mixture was extracted with ethyl acetate (15 mL × 3), the organic phase was taken, and the mixture was washed with water (10 mL × 2) and saturated sodium chloride solution (10 mL), respectively. The target compound WX014-2 was obtained after rotationally drying the organic phase.

Step 3: Synthesis of Compound WX014-3 Compound WX014-2 (0.33 g, 906.01 μmol), Compound BB-5 (296.43 mg, 906.01 μmol), Potassium Acetate (355.66 mg, 3.62 mmol), Pherocenate Palladium Chloride (132.59 mg,) 181.20 μmol) was dissolved in dioxane (10 mL) and water (1.5 mL), and the reaction solution was stirred at 100 ° C. for 1.5 hours under the protection of nitrogen gas. The reaction mixture was concentrated, N, N-dimethylformamide (5 mL) and a wastewater treatment agent solution (8 mL) were added, and the mixture was allowed to stand overnight. The filtrate was filtered and dried by rotation. Separation was performed by preparative HPLC to obtain the target compound WX014-3.

Step 4: Synthesis of Compounds WX014 and WX015 Compound WX014-3 is supercritical fluid chromatography (separation condition column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: Separation was performed by 40% -40%; flow rate: 50 mL / min) to obtain cis-trans isomers WX014 and WX015, and the retention times were 3.228 min and 3.513 min, respectively. According to NOE identification, WX014 is a cis isomer: ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.45 (s, 1H), 8.39 (s, 1H), 8.20 (s, 1H), 8.02- 8.04 (d, J = 8.8Hz, 1H), 7.77-7.81 (m, 2H), 7.70 (s, 1H), 4.88-4.92 (t, J = 8.8Hz, 1H), 3.82-3.87 (m, 1H) , 2.81-2.88 (m, 1H), 2.61-2.63 (m, 4H), 2.58 (s, 3H), 2.33 (s, 3H), 2.30 (s, 3H), 1.05-1.06 (d, J = 6.8Hz) , 6H), MS-ESI m / z: 567.1 [M + H] ⁺ . WX015 is a trans isomer: ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 8.51 (s, 1H), 8.27 (s, 1H), 8.20 (s, 1H), 7.99-8.01 (d, J = 8.4Hz, 1H), 7.75-7.81 (m, 2H), 7.69 (s, 1H), 5.27-5.31 (t, J = 9.2Hz, 1H), 3.88-3.93 (m, 1H), 2.99 (s, 1H) ), 2.74-2.79 (m, 3H), 2.67 (s, 1H), 2.56 (s, 3H), 2.33 (s, 6H), 1.07-1.08 (d, J = 6.8Hz, 6H), MS-ESI m / z: 567.1 [M + H] ⁺ .

Example 12: WX016, WX017

Step 1: Synthesis of compound WX016-1
WX014-1 (0.5 g, 1.55 mmol) was dissolved in N, N'-dimethylformamide (10.00 mL), followed by tetrahydropyrrole (121.05 mg, 1.70 mmol, 142.08 μL), tetramethylurea hexafluorophosphate (882.50 mg). , 2.32 mmol) and diisopropylethylamine (399.96 mg, 3.09 mmol, 539.03 μL) were added, the mixed solution was stirred at 25 ° C. for 5 hours under nitrogen gas protection, and after the reaction was completed, water (10.00 mL) was added to the reaction solution. The mixture was added, extracted 3 times with ethyl acetate (10.00 mL), the organic phase was washed with water (10.00 mL × 3) and saturated saline (10.00 mL), respectively, and further dried over anhydrous sodium sulfate. The organic phase was rotationally dried to obtain the target compound WX016-1.

Step 2: Synthesis of compound WX016-2
WX016-1 (0.55 g, 1.41 mmol,) was dissolved in dioxane (5 mL) and BB-7 (573.94 mg, 1.75 mmol), potassium acetate ((573.84 mg, 5.85 mmol)), in solution under nitrogen gas protection. Water (1.00 mL) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (213.92 mg, 292.36 μmol) were added, and the reaction solution was heated to 100 ° C. and stirred for 16 hours. After completion, the reaction solution was concentrated, dried by rotation, and separated by preparative HPLC to obtain the target compound WX016-2.

Step 3: Synthesis of WX016 and WX017
WX016-2 is separated by SFC (chromatography column: OD (250 mm * 30 mm, 10 μm), elution condition: [0.1% NH ₃ H ₂ O EtOH]; B%: 40% -40%; flow rate: 80 mL / min). Then, cis-trans isomers WX016 (Rt = 0.736 min) and WX017 (Rt = 0.946 min) were obtained. According to NOE identification, WX016 is a cis isomer: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.67 (s, 1H), 8.39 (s, 1H), 8.35 (s, 1H), 7.94 (s, 1H), 7.89-7.92 (m, 1H), 7.79 (d, J = 8.4Hz, 2H), 5.09-5.18 (m, 1H), 3.44-3.52 (m, 4H), 3.12-3.20 (m, 1H) , 2.73-2.83 (m, 2H), 2.66-2.70 (m, 2H), 2.66 (s, 3H), 2.46 (s, 3H), 2.42 (s, 3H), 1.98-2.01 (m, 2H), 1.87 -1.91 (m, 2H). WX017 is a trans isomer: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.70 (s, 1H), 8.44 (s, 1H), 8.12 (s, 1H), 7.98 (s, 1H), 7.95-7.97 (m, 1H), 7.80-7.83 (m, 1H), 5.11-5.15 (m, 1H), 3.53-3.57 (m, 2H), 3.37-3.39 (m, 3H), 2.91-2.95 (s, 4H) , 2.69 (s, 3H), 2.46 (s, 3H), 2.44 (s, 3H), 1.89-1.92 (m, 4H).

Example 13: WX018, WX019

Step 1: Synthesis of Compound WX018-2 Compound BB-1 (50.00 mg, 222.18 μmol), WX018-1 (80.44 mg, 444.36 μmol) and cesium carbonate (144.78 mg, 444.36 μmol) in N, N-dimethylformamide methyl acetal It was dissolved in (5 mL), heated to 100 ° C. with microwaves, and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, and the residue was separated by a preparative chromatography plate (eluent: petroleum ether / ethyl acetate = 3: 1) to obtain the target compound WX018-2. .. MS-ESI m / z: 324.8 [M + H] ⁺ , 326.8 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX018-3 Compound WX018-2 (60.02 mg, 141.47 μmol), BB-3 (65.44 mg, 141.47 μmol), potassium acetate (55.53 mg, 565.88 μmol) was added to dioxane (2 mL) and water (2 mL). It was dissolved in 0.2 mL), after which Pd (dppf) Cl2 (2.07 mg, 2.83 μmol) was added, and the mixture was heated to 95 ° C. under the protection of nitrogen gas and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, and the residue was separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 20: 0.02), and the target compound was WX018-3. Got MS-ESI m / z: 561.0 [M + H] ⁺ , 563.0 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX018-4
Ammonia was introduced into a methanol (30 mL) solution at 0 ° C. for about 30 minutes. WX018-3 (190.00 mg, 284.06 μmol) was dissolved in the ammonia-methanol solution, heated to 80 ° C., and stirred for 16 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, the residue was separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 20: 0.2), and further, an HPLC preparative column was used. Separation was performed by n (AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: 40% -40%, min) to obtain the target compound WX018-4.

Step 4: Synthesis of Compounds WX018 and WX019 Compound WX018-4 is supercritical fluid chromatography (separation condition column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: Separation by 40% -40%) gave enantiomers WX018 (retention time: 4.861 min) and WX019 (retention time: 5.517 min). WX018: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.31 (d, J = 2.0 Hz, 1H), 8.15 --8.05 (m, 3H), 7.98 (d, J = 2.3 Hz, 1H), 7.90 --7.69 ( m, 2H), 7.28 (br s, 1H), 7.19 --7.00 (m, 1H), 5.58 (br s, 1H), 5.40 --5.23 (m, 1H), 4.28 --4.12 (m, 1H), 4.12 - 4.01 (m, 1H), 3.98 (s, 3H), 3.10 (br dd, J = 7.4, 14.4 Hz, 1H), 1.33 (d, J = 7.0 Hz, 3H). MS-ESI m / z: 546.1 [M + H] ⁺ , 548.1 [M + H + 2] ⁺ . WX019: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.31 (d, J = 2.0 Hz, 1H), 8.16 --8.08 (m, 3H), 7.97 (d, J = 2.0 Hz, 1H), 7.88 --7.81 ( m, 1H), 7.80 --7.71 (m, 1H), 7.27 (d, J = 2.5 Hz, 1H), 7.16 --7.05 (m, 1H), 5.63 (br s, 1H), 5.35 (br s, 1H) , 4.25 --4.13 (m, 1H), 4.12 --4.02 (m, 1H), 3.98 (s, 3H), 3.10 (br dd, J = 6.8, 13.8 Hz, 1H), 1.33 (d, J = 7.0 Hz, 3H). MS-ESI m / z: 546.1 [M + H] ⁺ , 548.1 [M + H + 2] ⁺ . The proportion was 1: 1.

Example 14: WX020

Step 1: Synthesis of compound WX020-3
WX020-1 (500.00 mg, 2.03 mmol), WX020-2 (350.00 mg, 2.09 mmol, 1.0HCl), triethylamine (1.00 g, 9.89 mmol), 2-hydroxypyridine N-oxide (250.00 mg, 2.25 mmol) and 1 -(3-Dimethylaminopropyl) -3-acetoaldehyde hydrochloride (500.00 mg, 2.61 mmol) was dissolved in methylene chloride (30.00 mL), stirred with circulation and reacted for 16 hours. After completion of the reaction, the reaction was washed with water (20 mL), the aqueous phase was extracted with methylene chloride (20 mL), the organic phases were combined and concentrated, and the obtained residue was obtained by a chromatography column (eluent: petroleum ether /). Separation with ethyl acetate = 0% -25%) gave the target compound WX020-3. MS-ESI m / z: 358.9 [M + H] ⁺ , 360.9 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX020-4 A formic acid solution (10.00 mL) of iron powder (300.00 mg, 5.37 mmol) and compound WX020-3 (200.00 mg, 507.39 μmol) was stirred at 100 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound WX020-4, which was used as it was in the next step. MS-ESI m / z: 339.0 [M + H] ⁺ , 341.0 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX020-5
A mixed solution of WX020-4 (400.00 mg, 1.18 mmol) and sodium hydroxide (600.00 mg, 15.00 mmol) in methanol (15 mL) and water (15 mL) was stirred at 25 ° C. and reacted for 16 hours. After that, the mixture was heated to 70 ° C., further stirred and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to remove the solvent methanol. The aqueous phase was neutralized with 1.0 M aqueous hydrochloric acid solution until the pH value reached 5-6. At this time, the mixture was extracted twice with ethyl acetate (20 mL). The organic phases were combined, dried over anhydrous sodium sulfate and filtered. The filtrate was distilled under reduced pressure to obtain the target compound WX020-5, which was used as it was in the next step. MS-ESI m / z: 325.0 [M + H] ⁺ , 327.0 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX020-6
Oxalyl chloride (139.83 mg, 1.10 mmol) was added to a solution of WX020-5 (180.00 mg) in methylene chloride (30 mL). The reaction mixture was stirred at 20 ° C. for 1 hour. The solution was then bubbled with ammonia for 10 minutes. The reaction solution was stirred and reacted for 15 hours. After completion of the reaction, the reaction solution was washed once with water (15 mL), the organic phase was concentrated under reduced pressure to obtain WX020-6, which was used as it was in the next step. MS-ESI m / z: 323.9 [M + H] ⁺ , 325.9 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX020
WX020-6 (100.00 mg, 181.17 μmol), BB-3 (80.00 mg, 172.97 μmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (15.00 mg, 20.50 μmol) and acetate A mixed solution of potassium (15.00 mg, 20.50 μmol) dioxane (5 mL) and water (1 mL) was stirred and reacted at 100 ° C. for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was washed with water (10 mL) and extracted with methylene chloride (10 mL × 2). The organic phase was distilled under reduced pressure and the resulting residue was subjected to high performance liquid chromatography (Kromasil 150 * 25mm * 10μμm; mobile phase: [water-water (0.05% ammonium hydroxide ammonium hydroxide v / v) -ACN]; B%: 13% -43%, 8 min) was separated to obtain the target compound WX020. ^{1 1} H NMR (400 MHz, DMSO-d6) δ: 8.16 (s, 1 H) 8.02 --8.10 (m, 2 H) 7.88 (dd, J = 8.53, 2.26 Hz, 1 H) 7.65 --7.73 (m, 2) H) 7.47 (d, J = 2.26 Hz, 1 H) 7.37 (dd, J = 8.78, 2.51 Hz, 1 H) 7.21 --7.29 (m, 2 H) 7.12 (s, 1 H) 6.07 (br s, 1 H) 4.16 (s, 2 H) 3.81 (s, 3 H) 1.15 (s, 6 H). MS-ESI m / z: 560.0 [M + H] ⁺ .

Example 15: WX021

Step 1: Synthesis of compound WX021-3
WX021-1 (400.00 mg, 1.85 mmol), WX021-2 (314.00 mg, 1.87 mmol, 1.0HCl), triethylamine (600.00 mg, 5.93 mmol), 2-hydroxypyridine N-oxide (210.00 mg, 1.89 mmol) and 1 -(3-Dimethylaminopropyl) -3-acetoaldehyde hydrochloride (375.00 mg, 1.96 mmol) was dissolved in methylene chloride (50 mL), stirred at 50 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was washed with water (50 mL), the organic phase was concentrated to obtain the target compound WX021-3, which was used as it was in the next step.

Step 2: Synthesis of compound WX021-4
A solution of WX021-3 (1000.00 mg, 3.04 mmol) in formic acid (20 mL) was stirred at 100 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound WX021-4, which was used as it was in the next step. MS-ESI m / z: 339.0 [M + H] ⁺ , 341.0 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX021-5
A mixed solution of WX021-4 (1.0 g, 3.10 mmol) and lithium hydroxide monohydrate (1.30 g, 31.00 mmol) in methanol (30 mL) and water (40 mL) was stirred at 20 ° C and reacted for 16 hours. It was. After completion of the reaction, the nitrogen gas stream was bubbled to remove the solvent methanol. The aqueous phase was neutralized with a 1.0 M aqueous hydrochloric acid solution until the pH reached 3-4. The white solid precipitate was collected by filtration and dried to obtain the target compound WX021-5, which was used as it was in the next step. MS-ESI m / z: 325.0 [M + H] ⁺ , 327.0 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX021-6
Oxalyl chloride (362.50 mg, 2.86 mmol) was added to a solution of WX021-5 (450.00 mg, 1.38 mmol) in methylene chloride (20 mL). The reaction was stirred at 20 ° C. for 2 hours. The solution was then bubbled with ammonia for 30 minutes at -30 ° C. The reaction solution was stirred at 20 ° C. and reacted for 15 hours. After completion of the reaction, the reaction solution was washed once with water (30 mL), the aqueous phase was extracted with methylene chloride (30 mL × 2), and the organic phase was concentrated under reduced pressure to obtain WX021-6. Used in the process of. MS-ESI m / z: 323.9 [M + H] ⁺ , 325.9 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX021
WX021-6 (500.00 mg, 1.54 mmol), BB-3 (430.00 mg, 1.00 mmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (135.22 mg, 184.80 μmol) and acetate A mixed solution of potassium (700.00 mg, 7.13 mmol) dioxane (20 mL) and water (4 mL) was stirred and reacted at 100 ° C. for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was washed with water (30 mL) and extracted with methylene chloride (30 mL × 2). The organic phase is distilled under reduced pressure and the resulting residue is subjected to high performance liquid chromatography (Xtimate C18 150 * 25mm * 5μμm; mobile phase: [water / water (0.225% FA) -ACN]; B%: 46% -46. %, 12 min) to obtain the target compound WX021. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ: 10.27 (s, 1 H) 8.40 (s, 1 H) 8.15 --8.30 (m, 2 H) 8.04 --8.13 (m, 1 H) 7.88 --7.99 ( m, 2 H) 7.76 (d, J = 8.53 Hz, 2 H) 7.30 --7.52 (m, 2 H) 6.95 (br s, 1 H) 4.15 (dd, J = 12.92, 4.14 Hz, 1 H) 3.85- 4.00 (m, 1 H) 3.70 (s, 3 H) 2.74 (br d, J = 3.76 Hz, 1 H) 1.37 --1.67 (m, 1 H) 1.35 --1.64 (m, 1 H) 0.91 (t, J) = 7.40 Hz, 3 H). MS-ESI m / z: 560.2 [M + H] ⁺ .

Example 16: WX022

Step 1: Synthesis of compound WX022-3
WX022-1 (400.00 mg, 1.85 mmol), WX022-2 (340.00 mg, 1.87 mmol, 1.0HCl), triethylamine (600.00 mg, 5.93 mmol), 2-hydroxypyridine N-oxide (210.00 mg, 1.89 mmol) and 1 -(3-Dimethylaminopropyl) -3-acetaldehyde hydrochloride (370.00 mg, 1.93 mmol) was dissolved in methylene chloride (50 mL), stirred at 50 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was washed with water (50 mL), the organic phase was concentrated to obtain the target compound WX022-3, which was used as it was in the next step.

Step 2: Synthesis of compound WX022-4
A solution of WX022-3 (1000.00 mg, 2.91 mmol) in formic acid (24.38 mL) was stirred at 100 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound WX022-4, which was used as it was in the next step. MS-ESI m / z: 353.0 [M + H] ⁺ , 355.0 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX022-5
A mixed solution of WX022-4 (1.0 g, 2.83 mmol) and lithium hydroxide monohydrate (1.19 g, 28.30 mmol) in methanol (30.00 mL) and water (30.00 mL) was stirred at 20 ° C and reacted for 16 hours. It was. After completion of the reaction, the solvent methanol was removed by bubbling a nitrogen gas stream. The aqueous phase was neutralized with 1.0 M aqueous hydrochloric acid solution until the pH value reached 3-4. The aqueous phase was extracted with ethyl acetate (30 mL × 3), the organic phases were combined and rotationally dried to obtain the target compound WX022-5, which was used as it was in the next step. MS-ESI m / z: 339.0 [M + H] ⁺ , 341.0 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX022-6
Oxalyl chloride (580 mg, 4.57 mmol) was added to a solution of WX022-5 (1000.00 mg, 2.95 mmol) in methylene chloride (30 mL). The reaction was stirred at 20 ° C. for 2 hours. The solution was then bubbled with ammonia at -30 ° C for 30 minutes. The reaction solution was stirred at 20 ° C. and reacted for 15.5 hours. After completion of the reaction, the reaction solution was washed once with water (30 mL), the aqueous phase was extracted with methylene chloride (30 mL × 2), and the organic phase was concentrated under reduced pressure to obtain WX022-6. Used in the process of. MS-ESI m / z: 338.1 [M + H] ⁺ , 340.0 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX022
WX022-6 (400.00 mg, 1.18 mmol), BB-3 (400.00 mg, 893.18 μmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (100.00 mg, 136.67 μmol) and acetate A mixed solution of potassium (500.00 mg, 5.09 mmol) dioxane (20 mL) and water (4 mL) was stirred and reacted at 100 ° C. for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was washed with water (30 mL) and extracted with methylene chloride (30 mL × 2). The organic phase is distilled under reduced pressure and the resulting residue is subjected to high performance liquid chromatography (Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.225% FA) -ACN]; B%: 44% -54%. , 12 min) to obtain the target compound WX022. ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.09 --8.19 (m, 3 H) 8.06 (d, J = 2.20 Hz, 1 H) 7.90 (d, J = 2.20 Hz, 1 H) 7.70 --7.78 ( m, 1 H) 7.60 --7.68 (m, 2 H) 7.21 --7.35 (m, 1 H) 7.11 (ddd, J = 8.89, 7.51, 2.42 Hz, 1 H) 5.81 --6.34 (m, 2 H) 4.49 ( dd, J = 12.98, 3.52 Hz, 1 H) 3.81 --4.05 (m, 4 H) 2.85 (ddd, J = 10.78, 7.43, 3.58 Hz, 1 H) 1.91 --2.17 (m, 1 H) 1.04 --1.23 ( m, 6 H). MS-ESI m / z: 574.1 [M + H] ⁺ .

Example 17: WX023

Step 1: Synthesis of compound WX023-3
WX023-1 (500.00 mg, 2.31 mmol), WX023-2 (375.00 mg, 2.62 mmol, 1.0HCl), triethylamine (800.00 mg, 7.90 mmol), 2-hydroxypyridine N-oxide (300.00 mg, 2.70 mmol) and 1 -(3-Dimethylaminopropyl) -3-acetaldehyde hydrochloride (450.00 mg, 2.35 mmol) was dissolved in methylene chloride (50.00 mL), stirred at 50 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was washed with water (50 mL), the organic phase was concentrated to obtain the target compound WX023-3, which was used as it was in the next step. MS-ESI m / z: 341.0 [M + H] ⁺ , 343.0 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX023-4
A solution of WX023-3 (1000.00 mg) in formic acid (20 mL) was stirred at 100 ° C. and reacted for 16 hours. After completion of the reaction, the mixture was concentrated under reduced pressure to obtain the target compound WX023-4, which was used as it was in the next step. MS-ESI m / z: 351.0 [M + H] ⁺ , 353.0 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX023-5
A mixed solution of WX023-4 (0.5 g, 276.92 μmol) and lithium hydroxide monohydrate (120 mg, 2.86 mmol) in methanol (20.00 mL) and water (25.00 mL) was stirred at 20 ° C and reacted for 16 hours. It was. After completion of the reaction, the solvent methanol was removed by bubbling a nitrogen gas stream. The aqueous phase was neutralized with 1.0 M aqueous hydrochloric acid solution until the pH value reached 3-4. The cake was filtered, and the cake was spin-dried to obtain the target compound WX023-5, which was used as it was in the next step. MS-ESI m / z: 323.0 [M + H] ⁺ , 325.0 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX023-6
Oxalyl chloride (362.50 mg, 2.86 mmol) was added to a solution of WX023-5 (450.00 mg, 1.39 mmol) in methylene chloride (20 mL). The reaction was stirred at 20 ° C. for 2 hours. The solution was then bubbled with ammonia at -30 ° C for 30 minutes. The reaction solution was stirred at 20 ° C. and reacted for 15.5 hours. After completion of the reaction, the reaction solution was washed once with water (30 mL), the aqueous phase was extracted with methylene chloride (30 mL * 2), and the organic phase was concentrated under reduced pressure to obtain WX023-6. Used in the process of. MS-ESI m / z: 322.0 [M + H] ⁺ , 324.0 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX023
WX023-6 (450.00 mg, 1.40 mmol), BB-3 (430.00 mg, 1000 μmol), [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (125.00 mg, 170.83 μmol) and acetate A mixed solution of potassium (600.00 mg, 6.11 mmol) dioxane (20 mL) and water (4 mL) was stirred and reacted at 100 ° C. for 2 hours under nitrogen gas protection. After completion of the reaction, the mixture was washed with water (30 mL) and extracted with methylene chloride (30 mL × 2). The organic phase is distilled under reduced pressure and the resulting residue is subjected to high performance liquid chromatography (Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.225% FA) -ACN]; B%: 40% -50%. , 12 min) to obtain the target compound WX023. ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ: 9.52 --.10.62 (m, 1 H) 8.52 (s, 1 H) 8.40 (d, J = 2.26 Hz, 1 H) 8.25 (d, J = 2.26 Hz , 1 H) 8.04 --8.12 (m, 1 H) 7.88 --7.99 (m, 2 H) 7.71 --7.79 (m, 2 H) 7.36 (td, J = 8.53, 2.51 Hz, 1 H) 6.89 --7.09 (m) , 2 H) 4.24 (s, 2 H) 3.70 (s, 3 H) 1.14 (s, 4 H). MS-ESI m / z: 558.1 [M + H] ⁺ .

Example 18: WX024, WX025

Step 1: Synthesis of compound WX024-1
A solution of BB-2 (300.00 mg, 863.44 μmol, purity: 97.62%) and lithium hydroxide monohydrate (362.00 mg, 8.63 mmol) in ethanol (5.00 mL) and water (5.00 mL) was stirred at 25 ° C. It was allowed to react for 16 hours. After completion of the reaction, the reaction solution was adjusted with a 1.0 M aqueous hydrochloric acid solution until the pH value reached 3-4. After that, water (50 mL) was added to the reaction mixture for washing, and the mixture was further extracted once with ethyl acetate (50 mL). The organic phase was distilled under reduced pressure to give the target compound WX024-1. MS-ESI m / z: 310.8 [M + H] ⁺ , 312.8 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX024-2
Oxalyl chloride (156.60 mg, 1.23 mmol) was added to a solution of WX024-1 (150.00 mg, 411.19 μmol) in methylene chloride (20.00 mL). The reaction mixture was stirred at 20 ° C. for 1 hour. The solution was then bubbled with ammonia for 20 minutes. The reaction mixture was stirred at 20 ° C. and reacted for 16 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was extracted with methylene chloride (50 mL). The organic phases were combined and concentrated under reduced pressure to obtain WX024-2, which was used as it was in the next step. MS-ESI m / z: 309.9 [M + H] ⁺ , 311.9 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX024-3
WX024-2 (100.00 mg, 322.42 μmol), BB-10 (205.00 mg, 481.98 μmol), potassium acetate (126.00 mg, 1.28 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (24.00 mg, 32.80 μmol) dioxane (4.0 mL) and water (0.8 mL) suspension was replaced with nitrogen gas three times, after which the reaction was heated to 100 ^o C under nitrogen gas protection 40 Stirred for minutes. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurried with water (50 mL), washed and then extracted with methylene chloride (50 mL). The organic phase was spin dried. Separation by high performance liquid chromatography (chromatography column: Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (0.05% ammonium hydroxide v / v) -ACN]; B%: 8% -38%, 10min) The compound WX024-3 was obtained.

Step 4: Synthesis of WX024 and WX025
WX024-3 is separated by SFC (chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: 40% -40%) and enantiomer WX024 (Rt). = 0.981 min) and WX025 (Rt = 1.359 min) were obtained. WX024: ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.21 (d, J = 2.01 Hz, 1 H) 8.07 --8.12 (m, 2 H) 7.95 (d, J = 2.26 Hz, 1 H) 7.77 ( dd, J = 8.53, 2.01 Hz, 1 H) 7.66 (d, J = 8.53 Hz, 1 H) 6.14 (br s, 1 H) 5.74 (br s, 1 H) 4.06 --4.19 (m, 1 H) 3.97 (dd, J = 13.30, 9.54 Hz, 1 H) 3.87 (s, 3 H) 2.99 --3.15 (m, 1 H) 2.51 --2.64 (m, 3 H) 2.47 (s, 3 H) 1.25 (d, J) = 7.03 Hz, 3 H), MS-ESI m / z: 529.1 [M + H] ⁺ , 551.1 [M + Na] ⁺ . WX025: ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.14 --8.25 (m, 1 H) 8.09 (s, 2 H) 7.93 (d, J = 1.51 Hz, 1 H) 7.76 (dd, J = 8.41 , 1.63 Hz, 1 H) 7.65 (d, J = 8.53 Hz, 1 H) 6.24 (br s, 1 H) 5.83 (br s, 1 H) 4.08 --4.17 (m, 1 H) 3.97 (br dd, J = 13.18, 9.66 Hz, 1 H) 3.77 (br s, 1 H) 3.87 (s, 2 H) 2.98 --3.17 (m, 1 H) 2.37 --2.62 (m, 6 H) 1.25 (br d, J = 7.03 Hz, 3 H), MS-ESI m / z: 529.1 [M + H] ⁺ , 551.1 [M + Na] ⁺ .

Example 19: WX026, WX027

Step 1: Synthesis of compound WX026-1
At 0 ° C., a solution of 3-methylthiophene (300.00 mg, 3.06 mmol) in chloroform (3 mL) was added to a solution of chlorosulfonic acid (1.07 g, 9.18 mmol) in chloroform (7 mL). The reaction mixture was stirred at 0 ° C. and reacted for 1 hour. After completion of the reaction, the mixture was added dropwise to the stirred ice-water mixture (50 mL). After that, it was extracted twice with chloroform (50 mL). The organic phase was distilled under reduced pressure to obtain the target compound WX026-1. ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ: 7.67 (d, J = 5.27 Hz, 1 H) 7.02 (d, J = 5.02 Hz, 1 H) 2.55-2.72 (m, 3 H).

Step 2: Synthesis of compound WX026-3
WX026-1 (230.00 mg, 1.17 mmol) was added dropwise to a solution of WX026-2 (218.00 mg, 1.17 mmol) in pyridine (1 mL) at 25 ° C. within 10 minutes. The reaction was stirred at 25 ° C. for 16 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, and the mixture was further extracted with methylene chloride (50 mL). The organic phase was concentrated under reduced pressure to give WX026-3. MS-ESI m / z: 346.8 [M + H] ⁺ , 348.8 [M + H + 2] ⁺ ; ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.54 (br d, J = 4.27 Hz, 1 H ) 8.31 (d, J = 2.01 Hz, 1 H) 7.80 (d, J = 2.01 Hz, 1 H) 7.47 --7.78 (m, 1 H) 7.40 (d, J = 5.02 Hz, 1 H) 7.20 --7.26 ( m, 1 H) 6.82 (d, J = 5.02 Hz, 1 H) 2.21 (d, J = 3.26 Hz, 6 H).

Step 3: Synthesis of compound WX026-4
WX026-3 (350.00 mg, 758.66 μmol, purity: 75.27%), bis (pinacolato) diboron (289.00 mg, 1.14 mmol), potassium acetate (223.00 mg, 2.27 mmol) and [1,1'-bis (diphenylphosphino) ) Ferrocene] A suspension of dioxane (12 mL) of dichloropalladium (II) (55.00 mg, 75.17 μmol) was replaced with nitrogen gas three times, after which the reaction solution was heated to 100 ° C. under nitrogen gas protection 60. Stirred for minutes. After completion of the reaction, the reaction solution was concentrated and spin-dried together with the previous batch. The crude product was slurried with water (100 mL), washed, and then extracted with methylene chloride (100 mL). The organic phase was concentrated under reduced pressure to give WX026-4. MS-ESI m / z: 312.9 [M + H] ⁺ .

Step 4: Synthesis of compound WX026-5
WX024-2 (80.00 mg, 247.44 μmol), WX026-4 (201.00 mg, 246.87 μmol), potassium acetate (97.00 mg, 988.38 μmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (18.00 mg, 24.60 μmol) dioxane (4.0 mL) and water (0.8 mL) suspension was replaced with nitrogen gas three times, after which the reaction solution was heated to 100 ° C. under nitrogen gas protection for 60 minutes. Stirred. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurried with water (50 mL), washed and then extracted with methylene chloride (50 mL). The organic phase was spin dried. Separation was performed by column chromatography (MeOH: DCM = 0% to 10%) to obtain compound WX026-5.

Step 5: Synthesis of WX026 and WX027
WX026-5 was further separated by SFC (chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O MeOH]; B%: 55% -55%) and the target compound. WX026 (Rt = 1.438 min) and WX027 (Rt = 2.086 min) were obtained. WX026: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ: 8.43 (s, 1 H) 8.10 (br d, J = 2.76 Hz, 2 H) 7.62 --7.88 (m, 3 H) 7.33 --7.56 (m, 2 H) 6.84 (d, J = 5.02 Hz, 1 H) 6.00 (br s, 1 H) 5.37 --5.58 (m, 1 H) 5.48 (br s, 1 H) 4.10 --4.24 (m, 1 H) 4.15 (br dd, J = 13.18, 4.39 Hz, 1 H) 3.86 --4.00 (m, 1 H) 4.00 (s, 1 H) 3.19 (br s, 1 H) 2.07 --2.42 (m, 6 H) 1.28 (br d, J = 7.03 Hz, 3 H), MS-ESI m / z: 498.1 [M + H] ⁺ . WX027: ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.52 (br s, 1 H) 8.19 (br s, 2 H) 7.72 --8.00 (m, 3 H) 7.51 (br d, J = 4.02 Hz, 1 H) 6.93 (br d, J = 3.76 Hz, 1 H) 6.16 (br s, 1 H) 5.62 (br s, 1 H) 4.24 (br d, J = 10.29 Hz, 1 H) 4.07 (br t, J = 11.04 Hz, 1 H) 3.14 --3.40 (m, 1 H) 3.27 (br s, 1 H) 2.15 --2.48 (m, 1 H) 2.15 --2.48 (m, 5 H) 1.37 (br d, J = 6.27 Hz, 3 H), MS-ESI m / z: 498.1 [M + H] ⁺ .

Example 20: WX028, WX029

Step 1: Synthesis of compound WX028-1
WX024-2 (100.00 mg, 309.30 μmol), BB-4 (186.00 mg, 309.32 μmol), potassium acetate (121.00 mg, 1.23 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (23.00 mg, 31.43 μmol) dioxane (4.0 mL) and water (0.8 mL) suspension was replaced with nitrogen gas three times, after which the reaction solution was heated to 100 ° C. under nitrogen gas protection for 1 hour. Stirred. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurried with water (50 mL), washed and then extracted with methylene chloride (50 mL). The organic phase was spin dried. Separation by high performance liquid chromatography (chromatography column: Kromasil 150 * 25mm * 10μm; mobile phase: [water (0.05% ammonium hydroxide v / v) -ACN]; B%: 16% -26%, 8min) , Compound WX028-1 was obtained.

Step 2: Synthesis of WX028 and WX029
WX028-1 was separated by SFC (chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B%: 50% -50%) and enantiomer WX028 (Rt). = 3.739 min) and WX029 (Rt = 3.45 min) were obtained. WX028: ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.46 (s, 1 H) 8.18 (s, 1 H) 8.09 (s, 1 H) 8.03 (dd, J = 8.66, 5.90 Hz, 1 H) 7.65 --7.76 (m, 3 H) 7.22 --7.33 (m, 1 H) 7.03 --7.14 (m, 1 H) 5.64 (br s, 1 H) 5.22 --5.42 (m, 1 H) 4.06 --4.25 (m, m, 1 H) 3.86 --4.02 (m, 1 H) 3.07 (br d, J = 6.78 Hz, 1 H) 2.37 --2.62 (m, 3 H) 1.27 (d, J = 7.03 Hz, 3 H), MS-ESI m / z: 530.1 [M + H] ⁺ . WX029: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ: 8.44 (s, 1 H) 8.15 (s, 1 H) 8.10 (s, 1 H) 8.02 (dd, J = 9.03, 5.77 Hz, 1 H) 7.68 --7.74 (m, 3 H) 7.26 (dd, J = 8.03, 2.51 Hz, 1 H) 6.99 --7.12 (m, 1 H) 5.73 (br s, 1 H) 5.63 --5.84 (m, 1 H) 5.36 (br s, 1 H) 4.07 ―― 4.18 (m, 1 H) 4.07 ―― 4.18 (m, 1 H) 3.99 (dd, J = 13.30, 9.54 Hz, 1 H) 3.11 (br s, 1 H) 2.49 (s , 3 H) 1.27 (d, J = 7.03 Hz, 3 H), MS-ESI m / z: 530.1 [M + H] ⁺ .

Example 21: WX030, WX031

Step 1: Synthesis of compound WX030-1 Compound BB-2 (3.00 g, 9.23 mmol), BB-3 (4.08 g, 9.23 mmol), potassium acetate (3.62 g, 36.90 mmol) was added to dioxane (2 mL) and water (2 mL). It was dissolved in 0.2 mL), after which Pd (dppf) Cl ₂ (1.35 g, 1.85 mmol) was added, and the mixture was heated to 95 ° C. under the protection of nitrogen gas and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (50 mL), and extracted with methylene chloride (50 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure and separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15) to obtain the target compound WX030-1. Obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.35 (d, J = 2.0 Hz, 1H), 8.25 --8.10 (m, 2H), 7.99 (d, J = 2.3 Hz, 1H), 7.90 --7.71 (m, 2H), 7.71 --7.52 (m, 2H), 7.30 --7.28 (m, 1H), 7.20 --7.06 (m, 1H), 4.21 --4.10 (m, 4H), 4.03 (S, 3H), 3.26 --3.12 ( m, 1H), 1.34 (d, J = 7.0 Hz, 3H), 1.24 --1.18 (m, 3H). MS-ESI m / z: 575.1 [M + H] ⁺ , 577.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX030-2
WX030-1 (300.00 mg, 534.78 μmol) was dissolved in a methylamine alcohol solution (20 mL), heated to 80 ° C. and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, poured into water (50 mL), and extracted with methylene chloride (50 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent is removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 20: 0.2), and further separated by an HPLC preparative column (HPLC). Separation was performed by AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 30% -30%) to obtain the target compound WX030-2.

Step 3: Synthesis of Compounds WX030 and WX031 Compound WX030-2 is supercritical fluid chromatography (separation condition column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B%: 30. %-30%) to obtain enantiomers WX030 and WX031. The retention times were 4.092 min and 4.723 min, respectively, and the proportion was 1: 1. WX030: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.24 (d, J = 2.0 Hz, 1H), 8.14-8.04 (m, 3H), 7.91 (d, J = 2.3 Hz, 1H), 7.83 --7.65 ( m, 2H), 7.20 (d, J = 2.5 Hz, 1H), 7.11 --6.93 (m, 1H), 5.49 (br d, J = 4.5 Hz, 1H), 4.17 --4.05 (m, 1H), 4.04- 3.93 (m, 1H), 3.91 (s, 3H), 2.93 --2.81 (m, 1H), 2.67 (d, J = 5.0 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H). MS-ESI m / z: 560.2 [M + H] ⁺ , 562.0 [M + H + 2] ⁺ . WX031: ¹ HNMR (400MHz, CDCl ₃ ) δ: 8.24 (d, J = 2.0 Hz, 1H), 8.11 --7.99 (m, 3H), 7.91 (d, J = 2.3 Hz, 1H), 7.83 --7.73 (m) , 1H), 7.73 --7.65 (m, 1H), 7.46 (br s, 1H), 7.21 (s, 1H), 6.90 --6.90 (m, 1H), 5.47 (br d, J = 5.5 Hz, 1H), 4.15 --4.06 (m, 1H), 4.04 --3.93 (m, 1H), 3.91 (s, 3H), 2.95 --2.83 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H). MS-ESI m / z: 560.2 [M + H] ⁺ , 562.0 [M + H + 2] ⁺ .

Example 22: WX032, WX033

Step 1: Synthesis of compound WX032-1
WX024-2 (80.00 mg, 247.44 μmol), BB-5 (190.00 mg, 246.24 μmol), potassium acetate (97.00 mg, 988.38 μmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (18.00 mg, 24.60 μmol) dioxane (4.0 mL) and water (0.8 mL) suspension was replaced with nitrogen gas three times, after which the reaction solution was heated to 100 ° C. under nitrogen gas protection for 60 minutes. Stirred. After completion of the reaction, the reaction solution was concentrated and spin-dried. Water (50 mL) was added to the reaction mixture, and the mixture was extracted with methylene chloride (50 mL). The organic phase was distilled under reduced pressure and purified by column chromatography (MeOH: DCM = 0% to 10%) to obtain compound WX032-1.

Step 2: Synthesis of WX032 and WX033
WX032-1 was separated by SFC (chromatography column: OD (250 mm * 50 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OMeOH]; B%: 40% -40%) and enantiomer WX032 (Rt = 4.037 min) and WX033 (Rt = 4.298 min) were obtained. WX032: ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43 (br s, 1 H) 7.98 --8.17 (m, 2 H) 7.69 --7.83 (m, 2 H) 7.63 (br d, J = 8.53 Hz) , 1 H) 7.58 --7.66 (m, 1 H) 6.43 (br s, 1 H) 5.88 (br s, 1 H) 4.15 (br dd, J = 12.92, 3.89 Hz, 1 H) 3.89 --4.02 (m, 1 H) 3.19 (br s, 1 H) 2.58 (s, 3 H) 2.28 --2.45 (m, 6 H) 1.27 (br d, J = 6.78 Hz, 3 H), MS-ESI m / z: 513.1 [ M + H] ⁺ . WX033: ¹ H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.43 (br s, 1 H) 7.96 --8.82 (m, 2 H) 7.69 --7.81 (m, 2 H) 7.62 (br d, J = 8.03 Hz) , 1 H) 6.46 (br s, 1 H) 5.92 (br s, 1 H) 4.91 (s, 1 H) 4.15 (br d, J = 9.79 Hz, 1 H) 3.87 --4.03 (m, 1 H) 3.11. --3.29 (m, 1 H) 3.19 (br s, 1 H) 2.58 (s, 3 H) 2.23 --2.45 (m, 6 H) 1.21 --1.32 (m, 1 H) 1.21 --1.32 (m, 2 H) , MS-ESI m / z: 513.1 [M + H] ⁺ .

Example 23: WX034, WX035

Step 1: Synthesis of compound WX034-1 Crude product WX024-1 (100.00 mg), methylamine (80.00 mg, 643.92 μmol), triethylamine (129.94 mg, 1.28 mmol), 2-hydroxypyridine N-oxide (42.00 mg, 378.04 μmol) ) And 1- (3-Dimethylaminopropyl) -3-acetaldehyde hydrochloride (62.00 mg, 323.42 μmol) were dissolved in methylene chloride (5 mL) and reacted at 50 ° C. for 16 hours with stirring. After completion of the reaction, the mixture was washed with water (50 mL), extracted with methylene chloride (50 mL), and the organic phase was concentrated to obtain the target compound WX034-1, which was used as it was in the next step. MS-ESI m / z: 323.8 [M + H] ⁺ , 325.8 [M + H + 2] ⁺ .

Step 2: Synthesis of compound WX034-2
WX034-1 (100.00 mg, 289.76 μmol), BB-5 (142.00 mg, 290.17 μmol), potassium acetate (114.00 mg, 1.16 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (21.00 mg, 28.70 μmol) dioxane (4.0 mL) and water (0.8 mL) suspension was replaced with nitrogen gas three times, after which the reaction solution was heated to 100 ° C. under nitrogen gas protection for 60 minutes. Stirred. After completion of the reaction, the reaction solution was concentrated and spin-dried. Separation was performed by column chromatography (MeOH: DCM = 0% to 8%) to obtain the target compound WX034-2.

Step 3: Synthesis of compounds WX034 and WX035
WX034-2 was separated by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 35% -35%) and enantiomer WX034 (Rt =). 3.665 min) and WX035 (Rt = 3.986 min) were obtained. WX034: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.45 (s, 1 H) 8.09 (br d, J = 8.53 Hz, 2 H) 7.69 --7.87 (m, 3 H) 5.97 (br d, J) = 4.27 Hz, 1 H) 4.14 (br dd, J = 12.92, 4.39 Hz, 1 H) 3.92 --4.04 (m, 1 H) 3.04 (br s, 1 H) 2.98 --3.12 (m, 1 H) 2.55- 2.71 (m, 6 H) 2.29 --2.49 (m, 6 H) 1.24 (br d, J = 7.03 Hz, 3 H), MS-ESI m / z: 527.0 [M + H] ⁺ . WX035: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.44 (s, 1 H) 8.08 (br d, J = 15.06 Hz, 2 H) 7.70 --7.87 (m, 3 H) 6.03 (br s, 1 H) 4.15 (br dd, J = 13.18, 4.39 Hz, 1 H) 3.92 --4.06 (m, 1 H) 2.97 --3.14 (m, 1 H) 2.53 --2.71 (m, 5 H) 2.53 --2.71 (m,) 1 H) 2.29 --2.48 (m, 5 H) 2.39 (br s, 1 H) 1.24 (br d, J = 7.03 Hz, 3 H), MS-ESI m / z: 527.0 [M + H] ⁺ .

Example 24: WX036, WX037

Step 1: Synthesis of compound WX036-2 WX036-1 (5 g, 35.17 mmol, 4.35 mL) was dissolved in MeOH (150 mL) in a pre-dried 100 mL reaction vessel to ammonium acetate (27.11 g, 351.73 mmol). Sodium cyanoborohydride (22.10 g, 351.73 mmol) was added. The reaction was stirred at 70 ° C. for 2 hours. After completion of the reaction, 1N HCl was added to the reaction system to adjust the pH to 3, diluted with 100 mL ethyl acetate, separated, and then the aqueous phase was collected and the organic phase was discarded. The aqueous phase was adjusted to a pH of 11 with saturated Na ₂ CO ₃ and extracted with ethyl acetate (50 mL × 5). The organic phases were combined, washed with saturated brine (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give WX036-2.

Step 2: Synthesis of compound WX036-4 WX036-2 (4 g, 19.56 mmol) and WX036-3 (4.65 g, 21.51 mmol) were placed in a pre-dried 100 mL reaction bottle and dissolved in DCM (50 mL). HATU (11.15 g, 29.33 mmol) was added, finally DIEA (5.05 g, 39.11 mmol, 6.81 mL) was added at 0 ° C. and the reaction was stirred at 20 ° C. for 16 hours. After completion of the reaction, the reaction system was diluted with 100 mL water / 50 mL methylene chloride, separated, the organic phase was collected, and the aqueous phase was extracted with methylene chloride (50 mL × 3). Combine the organic phases, wash with saturated brine (200 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, slurried with methylene chloride (80 ml) / methanol (10 mL) / methyl tert-butyl ether 50 ml, and filter. The cakes were collected to obtain the target compound WX036-4. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.75 (dd, J = 1.4, 4.5 Hz, 1H), 8.48 (dd, J = 1.4, 8.4 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H) ), 7.56 --7.35 (m, 2H), 7.39 (d, J = 2.3 Hz, 2H), 7.28 (br d, J = 2.3 Hz, 1H), 6.68 (d, J = 8.9 Hz, 1H), 6.57 ( d, J = 8.7 Hz, 2H), 6.03 (br d, J = 6.1 Hz, 2H), 5.77 (br s, 2H), 5.50 (br s, 3H), 4.51 (quin, J = 7.6 Hz, 2H) , 3.72 (s, 6H), 2.81 (s, 2H), 2.72 (q, J = 8.1 Hz, 2H), 2.33 --2.20 (m, 2H), 2.14 --1.92 (m, 4H), 1.90 --1.75 (m) , 5H), 1.70 --1.54 (m, 9H), 1.52 --1.39 (m, 3H).

Step 3: Synthesis of Compound WX036-5 WX036-4 (3.6 g, 10.55 mmol) was dissolved in formic acid (33.99 g, 738.57 mmol, 27.86 mL) in a pre-dried 250 mL bite flask. The reaction was stirred at 100 ° C. for 16 hours. After completion of the reaction, formic acid was removed by rotary drying, diluted with 100 mL water / 100 mL ethyl acetate, separated, and then the organic phase was collected and the aqueous phase was extracted with ethyl acetate (50 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate and purify by column chromatography (methylene chloride: methanol = 1: 0-100: 1). The target compound WX036-5 was obtained. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 9.43 (br s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.97 (dd, J = 2.2, 8.6 Hz, 1H), 5.18 (q, J = 8.8 Hz, 1H), 3.68 (s, 3H), 3.57 (q, J = 8.8 Hz, 1H), 2.45 --2.27 (m, 3H), 2.23 - 2.11 (m, 1H), 2.07 --1.95 (m, 1H), 1.95 --1.84 (m, 1H).

Step 4: Synthesis of compound WX036-6 WX036-5 (800 mg, 2.28 mmol) was added to a pre-dried 40 mL reaction bottle and dissolved in a methanol solution of methylamine (30 mL). The reaction solution was stirred at 20 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate and purify by column chromatography (methylene chloride: methanol = 1: 0-20: 1). Then, the target compound WX036-6 was obtained. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.39 (d, J = 2.3 Hz, 1H), 8.11 (s, 1H), 7.84 (dd, J = 2.3, 8.7 Hz, 1H), 7.59 (d, J) = 8.7 Hz, 1H), 5.90 (br s, 1H), 4.95 (q, J = 8.2 Hz, 1H), 3.38 (q, J = 8.3 Hz, 1H), 2.80 (d, J = 4.9 Hz, 3H) , 2.41 --2.28 (m, 1H), 2.28 --2.04 (m, 4H), 2.03 --1.88 (m, 3H).

Step 5: Synthesis of compound WX036-7 Add WX036-6 (270 mg, 770.97 μmol), BB-3 (409.56 mg, 925.16 μmol) and methyl acetate (226.99 mg, 2.31 mmol) to a pre-dried 40 mL reaction bottle. Then, dioxane (5 mL) and water (0.5 mL) were added. It was replaced with nitrogen gas, and Pd (dppf) Cl ₂ (56.41 mg, 77.10 μmol) was added and further replaced with nitrogen gas. The reaction was stirred at 90 ° C. for 12 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and then perform preparative high performance liquid chromatography (method: chromatography column: Nano-micro Kromasil C18 100 * 30 mm). It was separated and purified by 5 μm; mobile phase: [water (0.1% TFA) -ACN]; B%: 35% -55%, 10 min) to obtain WX036-7.

Step 6: Synthesis of compounds WX036 and WX037
WX036-7 (0.5 g, 853.19 μmol) was separated by SFC (method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 34% -34%, 4 min). A pair of enantiomers WX036 (holding time: 1.10 min) and WX037 (holding time: 2.36 min) were obtained. WX036: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (d, J = 1.8 Hz, 1H), 8.16 --8.07 (m, 3H), 7.98 (d, J = 2.2 Hz, 1H), 7.89 --7.81 (m, 1H), 7.81 --7.74 (m, 1H), 7.55 (s, 1H), 7.28 --7.24 (m, 1H), 7.18 --7.05 (m, 1H), 5.91 (br s, 1H), 4.99 ( q, J = 8.0 Hz, 1H), 3.98 (s, 3H), 3.40 (br d, J = 7.7 Hz, 1H), 2.80 (d, J = 4.2 Hz, 3H), 2.39 --2.30 (m, 1H) , 2.24 (br s, 2H), 2.16 --2.05 (m, 1H), 2.03 --1.92 (m, 2H). ESI, m / z = 586.1 [M + 1]. WX037: 1H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (d, J = 2.0 Hz, 1H), 8.21 --8.06 (m, 3H), 7.98 (d, J = 2.2 Hz, 1H), 7.89 --7.80 ( m, 1H), 7.80 --7.73 (m, 1H), 7.55 (s, 1H), 7.28 --7.23 (m, 1H), 7.17 --7.04 (m, 1H), 5.91 (br d, J = 4.0 Hz, 1H) ), 4.98 (q, J = 8.2 Hz, 1H), 3.98 (s, 3H), 3.39 (q, J = 8.3 Hz, 1H), 2.80 (d, J = 4.9 Hz, 3H), 2.40 --2.30 (m) , 1H), 2.29 --2.18 (m, 2H), 2.16 --2.05 (m, 1H), 2.02 --1.91 (m, 2H). ESI, m / z = 586.1 [M + 1].

Example 25: WX038, WX039

Step 1: Synthesis of compound WX038-1
WX034-2 (260.00 mg, 525.42 μmol), BB-8 (300.00 mg, 446.06 μmol), potassium acetate (206.00 mg, 2.10 mmol) and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) ) (38.00 mg, 51.93 μmol) dioxane (10 mL) and water (2 mL) suspension was replaced with nitrogen gas three times, after which the reaction solution was heated to 100 ° C. under nitrogen gas protection for 1 hour. Stirred. After completion of the reaction, the reaction solution was concentrated and spin-dried. The crude product was slurried with water (100 mL), washed, and then extracted with methylene chloride (100 mL). Rotately dry the organic phase and perform high performance liquid chromatography (chromatography column :: Xtimate C18 150 * 25mm * 5μm; mobile phase: [water (10mM NH ₄ HCO ₃ ) -ACN]; B%: 19% -39% , 8 min) to obtain the target compound WX038-1.

Step 2: Synthesis of compounds WX038 and WX039
WX038-1 was separated by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 35% -35%) and enantiomer WX038 (Rt =). 4.003 min) and WX039 (Rt = 4.411 min) were obtained. WX038: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.74 (s, 1 H) 8.20 --8.39 (m, 2 H) 8.11 (dd, J = 8.53, 2.01 Hz, 1 H) 8.03 (dd, dd, J = 8.91, 5.90 Hz, 1 H) 7.95 (br d, J = 4.77 Hz, 1 H) 7.73 --7.88 (m, 3 H) 7.35 --7.50 (m, 1 H) 3.94 --4.19 (m, 2 H) 2.84 --2.96 (m, 1 H) 2.54 (br s, 3 H) 2.43 (s, 3 H) 1.14 (d, J = 7.03 Hz, 3 H), MS-ESI m / z: 544.0 [M + H] ⁺ . WX039: ^{1 1} H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.74 (s, 1 H) 8.22 --8.36 (m, 2 H) 8.11 (dd, J = 8.41, 1.88 Hz, 1 H) 8.03 (dd, dd, J = 8.78, 6.02 Hz, 1 H) 7.94 (br d, J = 4.52 Hz, 1 H) 7.72 --7.77 (m, 3 H) 7.43 (td, J = 8.34, 2.38 Hz, 1 H) 3.90 --4.22 ( m, 2 H) 2.83 --3.01 (m, 1 H) 2.54 (br s, 3 H) 2.43 (s, 3 H) 1.11 --1.17 (m, 3 H), MS-ESI m / z: 544.0 [M + H] ⁺ .

Example 26: WX040

Step 1: Synthesis of compound WX040-3 Compound WX040-1 (5.00 g, 32.14 mmol) and sodium bicarbonate (172.80 g, 80.00 mL) are dissolved in dioxane (120.00 mL) and WX040-2 (WX040-2) (in a nitrogen gas atmosphere). 21.04 g, 96.42 mmol, 22.15 mL) was added, and the mixture was stirred at 25 ° C. for 14 hours. The reaction mixture was filtered, the filtrate was concentrated by rotary drying, extracted with ethyl acetate (20 mL × 3), and the organic phase was concentrated by rotary drying. Obtained WX040-3. 1H NMR (400 MHz, CHLOROFORM-d) δ = 5.49 (s, 1H), 4.35 (s, 1H), 3.85-3.94 (m, 2H), 3.75 (s, 3H), 2.72-2.73 (m, 1H) , 1.42 (s, 9H).

Step 2: Synthesis of Compound WX040-4 Compound WX040-3 (7.00 g, 31.93 mmol) was dissolved in acetonitrile (120.00 mL) and 4-dimethylaminopyridine (780.18 mg, 6.39 mmol) at 0 ° C. under a nitrogen gas atmosphere. And WX040-2 (34.84 g, 159.65 mmol, 36.68 mL) were added and stirred at 25 ° C. for 15 minutes. After that, it was reacted at 60 ° C. for 12 hours. The reaction solution was concentrated. Separation was performed by silica gel plate chromatography (petroleum ether: ethyl acetate = 7: 1) to obtain WX040-4. 1H NMR (400 MHz, CHLOROFORM-d) δ = 6.32 (s, 1H), 5.62 (s, 1H), 3.77 (s, 3H), 1.44 (s, 18H).

Step 3: Synthesis of Compound WX040-5 Compound WX040-4 (6.55 g, 21.74 mmol), BB-1 (4.89 g, 21.74 mmol) and cesium carbonate (2.12 g, 6.52 mmol) are dissolved in acetonitrile (100.00 mL). , 90 ° C. for 12 hours. The reaction was filtered, the filtrate was collected and concentrated by rotary drying. It was separated and purified by a silica gel column (petroleum ether: ethyl acetate = 3: 1) to obtain WX040-5. ^{1 1} H NMR (400MHz, DMSO-d ₆ ) δ = 8.28 (s, 1H), 8.21-8.22 (d, J = 2.4Hz, 1H), 7.97-8.00 (dd, J = 8.8, 1H), 7.63-7.65 (d, J = 8.8Hz, 1H), 5.35-5.39 (m, 1H), 4.51-4.60 (m, 1H), 3.73 (s, 3H), 1.26 (s, 18H).

Step 4: Synthesis of compound WX040-6 Compound WX040-5 (2.00 g, 3.80 mmol) was dissolved in ethanol hydrochloride (4 M, 30.00 mL) and stirred at 20 ° C. for 4 hours. A precipitate was precipitated during stirring. The reaction was filtered and cakes were collected to give WX040-6.

Step 5: Synthesis of compound WX040-7
Ammonia was introduced to saturate with methanol (5.00 mL) at 0 ° C to prepare an ammonia / methanol solution and placed in a kettle packed at 0 ° C. Compound WX040-6 (100.00 mg, 275.78 μmol) was dissolved in methanol (1.00 mL), added to an ammonia / methanol solution at 0 ° C. under a nitrogen gas atmosphere, tightly sealed, and then reacted at 60 ° C. for 12 hours. .. The reaction solution was left overnight to precipitate colorless crystals. The reaction was filtered and cakes were collected to give WX040-7. ^{1 1} H NMR (400MHz, DMSO- d ₆ ) δ = 8.31 (s, 1H), 8.23-8.24 (d, J = 2Hz, 1H), 7.97-7.99 (m, 1H), 7.63-7.65 (m, 1H) , 7.52-7.54 (m, 1H), 7.17 (s, 1H), 4.26-4.31 (m, 1H), 3.77-3.83 (m, 1H), 3.17 (s, 2H).

Step 6: Synthesis of Compound WX040 Compound WX040-7 (80.00 mg, 257.13 μmol), Compound BB-3 (113.83 mg, 257.13 μmol), Potassium Acetate (100.94 mg, 1.03 mmol), Pherocenate Palladium Chloride (37.63 mg, 51.43 μmol) ) Was dissolved in dioxane (8.00 mL) and water (1 mL), and the reaction solution was stirred at 80 ° C. for 12 hours under the protection of nitrogen gas. The reaction was concentrated, slurried with water (20 mL), cakes were collected, N, N-dimethylformamide (7 mL) and wastewater treatment solution (5 mL) were added and left overnight. The filtrate was filtered and the filtrate was spin-dried. The target compound WX040 was obtained by separation by preparative HPLC. ^{1 1} H NMR (400MHz, DMSO- d ₆ ) δ = 8.31 (s, 1H), 8.26 (s, 1H), 8.24-8.25 (d, J = 2Hz, 1H), 8.06-8.08 (m, 1H), 7.95 -7.99 (m, 1H), 7.87 (s, 1H), 7.75-7.77 (d, J = 8.4Hz, 1H), 7.69-7.71 (m, 2H), 7.36-7.37 (m, 2H), 4.31-4.35 (m, 1H), 3.97-4.01 (m, 1H), 3.73-3.76 (m, 1H), 3.71 (s, 3H).

Example 27: WX041

Step 1: Synthesis of compound WX041-2.

WX041-1 (1.91 g, 10.67 mmol) was added to a solution of BB-1 (2.00 g, 8.89 mmol) and potassium carbonate (2.46 g, 17.78 mmol) in N, N-dimethylformamide (20.00 mL) in a 40 mL reaction bottle. .. After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours under the protection of nitrogen gas. After completion of the reaction, water (15 mL) was added to the reaction solution to quench the reaction, and the mixture was further extracted with methylene chloride (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 1) to give WX041-2.

Step 2: Synthesis of compound WX041-3.

Ozone was slowly bubbled into a 250 mL three-necked flask at -78 ° C. in a solution of WX041-2 (1 g, 3.09 mmol) in methylene chloride (50 mL) until the solution turned blue. Immediately, nitrogen gas was bubbled until the solution became colorless, and dimethyl sulfide (961.41 mg, 15.47 mmol, 1.14 mL) was further added. After completion of the addition, the reaction solution was naturally heated to 25 ° C. and stirred for 1 hour. The reaction mixture was directly spin-dried and purified by preparative TLC (petroleum ether: ethyl acetate = 0: 1) to give WX041-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.0 Hz, 1H), 7.97 --7.83 (m, 2H), 7.63 (d, J = 8.8 Hz, 1H), 5.24 (s, 2H) ), 3.97 (s, 3H), 2.77 --2.73 (m, 1H).

Step 3: Synthesis of compound WX041-4.

To a 40 mL reaction bottle was added (diethylamino) sulfatrifluoride (1.48 g, 9.18 mmol, 1.21 mL) to a solution of WX041-3 (630 mg, 1.84 mmol) in methylene chloride (1.00 mL). After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours under the protection of nitrogen gas. After completion of the reaction, the reaction solution was slowly poured into an ice-water mixture (20 mL) and further extracted with methylene chloride (20 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC (petroleum ether: ethyl acetate = 1: 1) to give WX041-4. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.4 Hz, 1H), 8.04 (s, 1H), 7.87 (dd, J = 2.0, 8.7 Hz, 1H), 7.61 (d, J) = 8.8 Hz, 1H), 4.62 (t, J = 13.0 Hz, 2H), 3.90 (s, 3H).

Step 4: Synthesis of compound WX041-5.

To a 40 mL reaction bottle, a methanol solution of ammonia (7 M, 1.15 mL) was added to a methanol (1 mL) solution of WX041-4 (140 mg, 403.33 μmol). After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours under the protection of nitrogen gas. The reaction solution was directly concentrated to obtain a crude product. The crude product was washed once with methyl tert-butyl ether (5 mL) to give WX041-5. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.44 (d, J = 2.2 Hz, 1H), 8.08 (s, 1H), 7.89 --7.85 (m, 1H), 7.61 (d, J = 8.4 Hz, 1H) ), 4.72 (t, J = 14.6 Hz, 2H).

Step 5: Synthesis of compound WX041.

Sodium bicarbonate (34.16) in a 1,4-dioxane: water = 10: 1 (1 mL) solution of BB-3 (60 mg, 135.53 μmol) and WX041-5 (45.01 mg, 135.53 μmol) in a 40 mL reaction bottle. mg, 406.60 μmol, 15.81 μL) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (9.92 mg, 13.55 μmol) were added. After completion of the addition, the reaction solution was stirred at 80 ° C. for 5 hours under the protection of nitrogen gas. The reaction mixture was cooled to room temperature, water (5 mL) was added to quench the reaction, and the mixture was further extracted with methylene chloride (10 mL * 3). The organic phases are combined, dried over anhydrous sodium sulfate, concentrated, purified by preparative TLC (methylene chloride: methanol = 15: 1), and then further preparative HPLC (HPLC_ET12919-102-P1A2, chromatography column: Luna C18). Purification with 100 * 30 mm 5 μm; mobile phase: [water (0.1% TFA) -ACN]; B%: 40% -60%, 10 min) gave WX041. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.45 --8.21 (m, 3H), 8.15 --7.98 (m, 3H), 7.82 (d, J = 8.2 Hz, 1H), 7.49 (br d, J = 8.2 Hz, 1H), 7.25 (br t, J = 7.8 Hz, 1H), 3.89 (d, J = 1.0 Hz, 3H).

Example 28: WX042, WX043

Step 1: Synthesis of compound WX042-1 Compound WX024-1 (0.2 g, 610.68 μmol), dimethylamine alcohol solution (445.00 mg, 3.26 mmol, 0.5 mL), carbodiimide (0.12 g, 625.97 μmol), 2-hydroxypyridine- N-oxide (0.07 g, 630.07 μmol) and triethylamine (363.50 mg, 3.59 mmol, 0.5 mL) were dissolved in methylene chloride (6 mL) and stirred at 50 ° C. for 16 hours. The reaction mixture was diluted with water (30 mL), extracted with methylene chloride (30 mL × 2), and the organic phase was rotationally dried to obtain the target compound WX042-1.

Step 2: Synthesis of compound WX042-2 Compound WX042-1 (0.15 g, 337.52 μmol), compound BB-5 (180.00 mg, 367.83 μmol), potassium acetate (132.50 mg, 1.35 mmol), ferrocene palladium chloride (49.39 mg,) 67.50 μmol) was dissolved in dioxane (10 mL) and water (2 mL), and the reaction solution was stirred at 105 ° C. for 2 hours under the protection of nitrogen gas. The reaction mixture was diluted with water (30 mL), further extracted with methylene chloride (30 mL × 2), the organic phase was spin-dried, and preparative HPLC (Kromasil 150 * 25 mm * 10 μm; mobile phase: [water (0.05% water)). Separation was performed by ammonium oxide v / v) -ACN]; B%: 13% -23%, 8 min) to obtain the target compound WX042-2.

Step 3: Synthesis of Compounds WX042 and WX043 Compound WX042-2 is supercritical fluid chromatography (separation conditions [chromatography column: OD-3 (100 mm * 4.6 mm, 3 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]. ]; B%: 40% -40%, 8min]) to obtain enantiomers WX042 and WX043 :. WX042: ^{1 1} H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 1.11 (d, J = 6.78 Hz, 3 H) 2.17 --2.28 (m, 3 H) 2.33 (s, 3 H) 2.58 (s, 3 H) ) 2.78 (s, 3 H) 2.93 (s, 3 H) 3.48 --3.57 (m, 1 H) 3.98 --4.12 (m, 2 H) 7.66 --7.80 (m, 2 H) 7.95 (dd, J = 8.53,) 2.26 Hz, 1 H) 8.16 --8.31 (m, 1 H) 8.16 --8.31 (m, 1 H) 8.58 (d, J = 2.26 Hz, 1 H). WX043: ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ ppm 1.11 (d, J = 6.78 Hz, 3 H) 2.17 --2.28 (m, 3 H) 2.33 (s, 3 H) 2.58 (s, 3 H) ) 2.78 (s, 3 H) 2.93 (s, 3 H) 3.48 --3.57 (m, 1 H) 3.98 --4.12 (m, 2 H) 7.66 --7.80 (m, 2 H) 7.95 (dd, J = 8.53,) 2.26 Hz, 1 H) 8.16 --8.31 (m, 1 H) 8.16 --8.31 (m, 1 H) 8.58 (d, J = 2.26 Hz, 1 H). The retention times were 4.001 min and 4.960 min, respectively, and the proportion was 1: 1.

Example 29: WX044, WX045

Step 1: Synthesis of compound WX044-1 Sodium boron acetate (1.67 g, 7.87 mmol) was added to a solution of WX041-3 (1.35 g, 3.93 mmol) in methylene chloride (13.5 mL) in a reaction bottle. After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours. Water (10 mL) was added to the reaction solution to quench the reaction, and the mixture was further extracted with methylene chloride (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC (petroleum ether: ethyl acetate = 0: 1) to give WX044-1. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.40 (d, J = 2.2 Hz, 1H), 8.08 --7.99 (m, 1H), 7.86 --7.78 (m, 1H), 7.58 (d, J = 8.8 Hz) , 1H), 7.38 (dd, J = 2.2, 8.6 Hz, 1H), 6.60 (d, J = 8.6 Hz, 1H), 4.86 --4.69 (m, 1H), 4.65 --4.53 (m, 1H), 4.51- 4.38 (m, 1H), 4.19 (dd, J = 6.4, 13.8 Hz, 1H), 4.05-3.91 (m, 1H), 3.87 (s, 3H).

Step 2: Synthesis of compound WX044-2 To a reaction bottle, a solution of WX044-1 (300 mg, 917.07 μmol) in tetrahydrofuran (10 mL) was added with a solution of methylamine (2 M, 9.17 mL) in tetrahydrofuran. After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours under the protection of nitrogen gas. The reaction solution was directly concentrated to obtain WX044-2, which was used as it was in the next reaction.

Step 3: Synthesis of compound WX044-3 1,4-dioxane: water = 10: 1 (3 mL) of BB-3 (200 mg, 451.78 μmol) and WX044-2 (147.35 mg, 451.78 μmol) in a reaction bottle. Sodium bicarbonate (113.86 mg, 1.36 mmol, 52.71 μL) and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (33.06 mg, 45.18 μmol) were added to the solution. After completion of the addition, the reaction solution was stirred at 100 ° C. for 8 hours under the protection of nitrogen gas. The reaction was cooled to room temperature, water (5 mL) was added to quench the reaction, and the mixture was further extracted with methylene chloride (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (methylene chloride: methanol = 15: 1) to give the desired compound WX044-3.

Step 4: Synthesis of compounds WX044 and WX045.

WX044-3 is purified by SFC (chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 40% -40%) and separated to obtain enantiomers, and further prep. -HPLC (min chromatography column: Luna C18 100 * 30mm 5 μm; mobile phase: [water (0.1% TFA) -ACN]; B%: 30% -60%, 10 min) and purified by WX044 (retention time:: 1.22 minutes) and WX045 (holding time: 2.61 minutes) were obtained. WX044: ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.36 --8.21 (m, 3H), 8.10 (dd, J = 5.7, 8.8 Hz, 1H), 8.04 --7.97 (m, 2H), 7.77 (d) , J = 8.4 Hz, 1H), 7.47 (dd, J = 2.6, 8.4 Hz, 1H), 7.26 --7.20 (m, 1H), 4.68 (dd, J = 4.0, 13.7 Hz, 1H), 4.45 (dd, J = 3.9, 8.3 Hz, 1H), 3.98 (dd, J = 8.4, 13.7 Hz, 1H), 3.86 (s, 3H), 2.78 (s, 3H). WX045: ^{1 1} H NMR (400MHz, METHANOL- d ₄ ) δ = 8.38 --8.26 (m, 2H), 8.22 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 6.0, 8.8 Hz, 1H), 8.05 --7.95 (m, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.46 (dd, J = 2.5, 8.5 Hz, 1H), 7.29 --7.19 (m, 1H), 4.68 (dd, J = 3.7, 13.7 Hz, 1H), 4.45 (dd, J = 3.8, 8.4 Hz, 1H), 3.98 (dd, J = 8.4, 13.8 Hz, 1H), 3.86 (s, 3H), 2.78 (s, 3H).

Example 30: WX046, WX047

Step 1: Synthesis of compound WX046-1.
To a 40 mL reaction bottle, add methyl iodide (1.30 g, 9.17 mmol, 570.91 μL) to a solution of WX044-1 (300 mg, 917.07 μmol) and silver oxide (2.13 g, 9.17 mmol) in acetonitrile (10 mL). did. After completion of the addition, the reaction solution was stirred at 80 ° C. for 12 hours under the protection of nitrogen gas. The reaction solution was filtered to obtain a mother liquor. The mother liquor was diluted with methylene chloride (50 mL) and washed once with water (10 mL). The organic phase was dried over anhydrous sodium sulfate, concentrated and purified by preparative TLC (petroleum ether: ethyl acetate = 1: 2) to give WX046-1.

Step 2: Synthesis of compound WX046-2.

To a 40 mL reaction bottle was added a solution of WX046-1 (100 mg, 293.12 μmol) in tetrahydrofuran (10 mL) to a solution of methylamine (2 M, 2.93 mL) in methanol (7 M, 1.15 mL). After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours under the protection of nitrogen gas. The reaction solution was directly concentrated to obtain WX046-2, which was used as it was in the next reaction. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.43 (d, J = 2.0 Hz, 1H), 8.06 (s, 1H), 7.83 (dd, J = 2.2, 8.6 Hz, 1H), 7.58 (d, J = 8.6 Hz, 1H), 6.60 (br s, 1H), 4.81 --4.62 (m, 1H), 4.10 --3.97 (m, 2H), 3.46 (s, 3H), 2.88 --2.81 (m, 2H), 2.89 --2.80 (m, 1H).

Step 3: Synthesis of compound WX046-3.

In a reaction bottle, a solution of WX046-2 (125 mg, 282.36 μmol) and BB-3 (96.05 mg, 282.36 μmol) in a 1,4-dioxane: water = 10: 1 (1 mL) solution [1,1'- Bis (diphenylphosphino) ferrocene] palladium (II) dichloride (20.66 mg, 28.24 μmol) and sodium bicarbonate (47.44 mg, 564.72 μmol, 21.96 μL) were added. After completion of the addition, the reaction solution was stirred at 100 ° C. for 8 hours under the protection of nitrogen gas. The reaction was cooled to room temperature, water (5 mL) was added to quench the reaction, and the mixture was further extracted with methylene chloride (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and purified by preparative TLC (methylene chloride: methanol = 15: 1) to give the desired compound WX046-3.

Step 4: Synthesis of compounds WX046 and WX047.

WX046-3 is purified by SFC (chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OMeOH]; B%: 30% -30%), separated and separated. Obtained an enantiomer. Further purified by prep-HPLC (chromatography column: Luna C18 100 * 30 mm 5 μm; mobile phase: [water (0.1% TFA) -ACN]; B%: 35% -60%, 10 min) and WX046 (retention time) : 3.31 minutes) and WX047 (holding time: 3.65 minutes) were obtained. WX046: ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.38 --8.91 (m, 3H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.04 --7.94 (m, 2H), 7.76 (d) , J = 8.6 Hz, 1H), 7.46 (dd, J = 2.4, 8.6 Hz, 1H), 7.28 --7.20 (m, 1H), 4.55 (dd, J = 4.2, 13.9 Hz, 1H), 4.20 --4.13 ( m, 1H), 4.11 --4.04 (m, 1H), 3.86 (s, 3H), 3.39 (s, 3H), 2.77 (s, 3H). WX047: ^{1 1} H NMR (400MHz, METHANOL- d ₄ ) δ = 8.35 --8.39 (m, 3H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.04 --7.96 (m, 2H), 7.77 (d) , J = 8.4 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.28 --7.17 (m, 1H), 4.55 (dd, J = 4.2, 13.7 Hz, 1H), 4.20 --4.12 ( m, 1H), 4.11 --4.04 (m, 1H), 3.87 (s, 3H), 3.39 (s, 3H), 2.77 (s, 3H).

Example 31: WX048, WX049

Step 1: Synthesis of compound WX048-1 Compound WX024-1 (0.5 g, 1.53 mmol), isopropylamine (859.99 mg, 14.55 mmol, 1.25 mL), carbodiimide (300.00 mg, 1.56 mmol), 2-hydroxypyridine-N- Oxide (175.00 mg, 1.58 mmol) and triethylamine (908.75 mg, 8.98 mmol, 1.25 mL) were dissolved in methylene chloride (20.00 mL) and further stirred at 50 ° C. for 16 hours. The reaction mixture was diluted with water (30 mL), extracted with methylene chloride (30 mL × 2), and the organic phase was rotationally dried to obtain the target compound WX048-1.

Step 2: Synthesis of compound WX048-2 Compound WX048-1 (0.5 g, 996.80 μmol), compound BB-5 (0.52 g, 1.06 mmol), potassium acetate (0.4 g, 4.08 mmol), palladium chloride (0.15 g,) 205.00 μmol) was dissolved in dioxane (10.00 mL) and water (2 mL), and the reaction solution was stirred at 105 ° C. for 2 hours under the protection of nitrogen gas. The reaction mixture was diluted with water (30 mL), further extracted with methylene chloride (30 mL × 2), the organic phase was spin-dried, and preparative HPLC (Phenomenex Gemini C18 250 * 50 mm 10 μm; mobile phase: [water (0.05 mL)). % Ammonium hydroxide v / v) -ACN]; B%: 22% -32%, 8min) to obtain the target compound WX048-2.

Step 3: Synthesis of Compounds WX048 and WX049 Compound WX048-2 is supercritical fluid chromatography (separation condition OD-3 (100 mm * 4.6 mm, 3 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B% : 40% -40%, 8 min) to obtain enantiomers WX048 and WX049.

WX048: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 0.75 (d, J = 6.53 Hz, 3 H) 0.94 (d, J = 6.53 Hz, 3 H) 1.06 --1.16 (m, 1 H) 1.12 (br d, J = 6.78 Hz, 2 H) 2.14 --2.39 (m, 6 H) 2.48 --2.70 (m, 3 H) 2.74 --2.93 (m, 1 H) 3.71 --3.94 (m, 2 H) 4.15 ( br dd, J = 13.18, 4.64 Hz, 1 H) 7.64 --7.78 (m, 2 H) 7.83 (br d, J = 7.53 Hz, 1 H) 7.94 (br dd, J = 8.41, 1.88 Hz, 1 H) 8.08 (s, 1 H) 8.26 (d, J = 1.76 Hz, 1 H) 8.47 --8.68 (m, 1 H). WX049: ¹ H NMR (400 MHz, METHANOL- d ₄ ) δ ppm 0.73 (d, J = 6.53 Hz, 3 H) 0.91 (d, J = 6.78 Hz, 3 H) 1.10 (d, J = 6.78 Hz, 3 H) 2.19 (s, 3 H) 2.30 (s, 3 H) 2.56 (s, 3 H) 2.71 --2.90 (m, 1 H) 3.66 --3.91 (m, 2 H) 4.12 (br dd, J = 13.30, 4.77 Hz, 1 H) 7.55 --7.71 (m, 1 H) 7.55 --7.71 (m, 1 H) 7.76 --7.84 (m, 1 H) 7.89 (dd, J = 8.28, 2.01 Hz, 1 H) 8.05 (s) , 1 H) 8.20 (d, J = 1.76 Hz, 1 H) 8.54 (d, J = 1.76 Hz, 1 H). The retention times were 3.471 min and 3.593 min, respectively, and the proportion was 1: 1.
Example 32: WX050, WX051

Step 1: Synthesis of compound WX050-3
WX050-1 (1.6 g, 12.11 mmol) is dissolved in methylene chloride (20.00 mL), and triethylamine (2.45 g, 24.21 mmol, 3.37 mL) and WX050-2 (2.77 g, 14.53 mmol) are added to the mixed solution. Was stirred at 25 ^o C for 10 hours and TLC (petroleum ether: ethyl acetate = 1: 1) showed that the reaction was complete. The reaction mixture was spin-dried and separated by a silica gel column (petroleum ether: ethyl acetate = 5: 1 to 3: 1) to obtain the target compound WX050-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ: 7.77 (d, J = 8.4Hz, 2H), 7.33 (d, J = 8Hz, 2H), 4.01-4.08 (m, 1H), 3.60 (s, 3H) , 2.41-2.44 (m, 3H), 2.40-2.41 (m, 1H), 1.88-1.93 (m, 2H), 1.18 (d, J = 7.2Hz, 2H).

Step 2: Synthesis of compound WX050-4
BB-1 (0.1 g, 444.36 μmol) is dissolved in N, N'-dimethylformamide (10.00 mL), which contains cesium carbonate (217.17 mg, 666.54 μmol) and WX050-3 (190.86 mg, 666.54 μmol, 208.66 μL). ) Is added and the reaction solution is stirred at 60 ° C. for 3 hours. After completion of the reaction, water (10.00 mL) is added to the reaction solution, and the mixture is extracted 3 times with ethyl acetate (10.00 mL) to remove the organic phase with water (10.00 mL). It was washed 3 times with (mL), washed with saturated brine (10.00 mL), further dried with anhydrous sodium sulfate, and the organic phase was rotationally dried to obtain the target compound WX050-4.

Step 3: Synthesis of compound WX050-5
WX050-4 (0.11 g, 324.31 μmol) is dissolved in methanol (3.00 mL) and water (1.00 mL), lithium hydroxide monohydrate (27.22 mg, 648.61 μmol) is added, and the reaction solution is added to 25. Stir at ° C. for 5 hours, and after completion of the reaction, spin dry the reaction solution, add water (10.00 mL) to it, wash with ethyl acetate (5.00 mL), and bring the aqueous phase to pH 5 with hydrochloric acid (1 M). Adjust and extract 3 times with ethyl acetate (5.00 mL), wash the organic phase with saturated brine (10.00 mL), dry with anhydrous sodium sulfate, spin dry the organic phase to give the desired compound WX050-5. Obtained. ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ = 8.42 (d, J = 2.3 Hz, 1 H), 8.22 (s, 1 H), 7.80 (dd, J = 8.7, 2.1 Hz, 1 H), 7.54 (d, J = 8.5 Hz, 1 H), 4.12 (br t, J = 7.0 Hz, 2 H), 2.53 --2.73 (m, 2 H), 1.66 --1.82 (m, 1 H), 1.24 (br d) , J = 7.0 Hz, 3 H).

Step 4: Synthesis of compound WX050-6
WX050-5 (0.1 g, 307.54 μmol) was dissolved in N, N'-dimethylformamide (3.00 mL), to which methylamine hydrochloride (31.15 mg, 461.32 μmol) and tetramethylurea hexafluorophosphate (175.41 mg,) were dissolved. 461.32 μmol) and diisopropylethylamine (158.99 mg, 1.23 mmol, 214.27 μL) were added, the reaction solution was stirred at 25 ° C. for 5 hours under the protection of nitrogen gas, and after the reaction was completed, water (10.00 mL) was added to the reaction solution. Then, extract 3 times with ethyl acetate (10.00 mL), wash the organic phase 3 times with water (10.00 mL), wash with saturated brine (10.00 mL), dry with anhydrous sodium sulfate, and rotate the organic phase. The mixture was dried to obtain the target compound WX050-6.

Step 5: Synthesis of compound WX050-7
WX050-6 (0.09 g, 266.12 μmol) was dissolved in dioxane (5.00 mL), to which [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (38.94 mg, 53.22 μmol), BB -3 (141.37 mg, 319.34 μmol) and potassium acetate (104.47 mg, 1.06 mmol) were added, the reaction solution was stirred at 100 ° C. for 3 hours under the protection of nitrogen gas, and after the reaction was completed, the reaction solution was rotationally dried. Separation was performed by preparative HPLC (formic acid system) to obtain the target compound WX050-7.

Step 6: Synthesis of compounds WX050 and WX051
WX050-7 is separated and purified by SFC (chromatography column: AD (250 mm * 30 mm, 10 μm), elution condition: 0.1% NH ₃ H ₂ OEtOH, B%: 55% -55%; flow rate: 80 mL / min). Then, the target compounds WX050 (Rt = 0.740 min) and WX051 (Rt = 1.656 min) were obtained. WX050: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ = 8.35 (d, J = 2.0 Hz, 1 H), 8.15 (d, J = 2.3 Hz, 1 H), 8.10 --8.14 (m, 1 H) , 8.08 (s, 1 H), 7.99 (d, J = 2.0 Hz, 1 H), 7.84 --7.88 (m, 1 H), 7.78 --7.82 (m, 1 H), 7.54 (s, 1 H), 7.28 (br d, J = 2.5 Hz, 1 H), 7.08 --7.15 (m, 1 H), 6.11 (br s, 1 H), 4.12 --4.32 (m, 1 H), 3.98 --4.00 (m, 3) H), 3.95 (s, 1 H), 2.86 (d, J = 4.8 Hz, 3 H), 2.28 --2.39 (m, 1 H), 2.13 --2.26 (m, 1 H), 1.89 (br dd, J) = 13.7, 3.9 Hz, 1 H), 1.21 (d, J = 6.8 Hz, 3 H). WX051: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ = 8.35 (d, J = 1.8 Hz, 1 H), 8.15 (d, J = 2.3 Hz, 1 H), 8.10 --8.14 (m, 1 H) , 8.08 (s, 1 H), 7.99 (d, J = 2.0 Hz, 1 H), 7.84 --7.99 (m, 1 H), 7.77 --7.83 (m, 1 H), 7.54 (s, 1 H), 7.28 (d, J = 2.5 Hz, 1 H), 7.07 --7.18 (m, 1 H), 6.11 (br s, 1 H), 4.16 --4.28 (m, 1 H), 3.98 --4.00 (m, 3 H) ), 3.95 (s, 1 H), 2.86 (d, J = 4.8 Hz, 3 H), 2.28 --2.38 (m, 1 H), 2.11 --2.26 (m, 1 H), 1.89 (br dd, J = 13.6, 4.5 Hz, 1 H), 1.21 (d, J = 7.0 Hz, 3 H).

Example 33: WX052, WX053

Step 1: Synthesis of compound WX052-1 Compound WX024-1 (0.5 g, 1.53 mmol), tetrahydropyrrole (127.80 mg, 1.80 mmol, 150.00 μL), tetramethylurea hexafluorophosphate (600.00 mg, 1.58 mmol), triethylamine ( 727.00 mg, 7.18 mmol, 1.00 mL) was dissolved in methylene chloride (20 mL) and stirred at 50 ° C. for 16 hours. After completion of the reaction, the reaction solution was diluted with water (30 mL), extracted with methylene chloride (30 mL × 2), and the organic phase was rotationally dried to obtain the target compound WX052-1.

Step 2: Synthesis of compound WX052-2 Compound WX052-1 (0.9 g, 1.29 mmol), compound BB-5 (702.13 mg, 1.37 mmol), potassium acetate (0.51 g, 5.19 mmol), ferrocene palladium chloride (0.19 g,) 259.46 μmol) was dissolved in dioxane (25 mL) and water (5 mL), and the reaction solution was stirred at 105 ° C. for 2 hours under the protection of nitrogen gas. After completion of the reaction, the reaction mixture was diluted with water (30 mL), further extracted with methylene chloride (30 mL × 2), the organic phase was rotationally dried, and preparative HPLC (Phenomenex Gemini C18 250 * 50 10u; mobile phase: [ Separation with water (0.05% ammonium hydroxide v / v) -ACN]; B%: 17% -27%, 8 min) gave the target compound WX052-2.

Step 3: Synthesis of Compounds WX052 and WX053 Compound WX052-2 is supercritical fluid chromatography (separation condition column: Phenomenex Gemini C18 250 * 50mm 10μ; mobile phase: [water (0.05% ammonium hydroxide v / v) -ACN]; B%: 17% -27%, 8 min) separated to give enantiomers WX052 and WX053. The retention times were 4.252 min and 4.909 min, respectively, and the proportion was 1: 1. WX052: ^{1 1} H NMR (400 MHz, METHANOL-d4) δ: 1.13 (d, J = 7.03 Hz, 3 H) 1.56 --1.84 (m, 4 H) 2.21 (s, 3 H) 2.32 (s, 3 H) 2.58 (s, 3 H) 3.21 --3.44 (m, 5 H) 3.95 --4.13 (m, 2 H) 7.61 --7.74 (m, 2 H) 7.93 (br d, J = 8.53 Hz, 1 H) 8.11 --8.24 (m, 2 H) 8.57 (s, 1 H). WX053: ¹ H NMR (400 MHz, METHANOL-d4) δ: 1.12 (d, J = 6.78 Hz, 3 H) 1.58 --1.83 (m, 4 H) 2.22 (s, 3 H) 2.32 (s, 3 H) 2.58 (s, 3 H) 3.22 --3.43 (m, 5 H) 3.94 --4.14 (m, 2 H) 7.62 --7.76 (m, 2 H) 7.92 (dd, J = 8.53, 1.76 Hz, 1 H) 8.13 - 8.25 (m, 2 H) 8.56 (s, 1 H).

Example 34: WX054, WX055

Step 1: Synthesis of Compound WX054-2 Compound WX024-1 (0.2 g, 642.82 μmol), WX054-1 (82.40 mg, 1.44 mmol, 0.1 mL), Carbodiimide (0.123 g, 641.62 μmol), 2-Hydroxypyridine-N -Oxide (0.084 g, 756.08 μmol) and triethylamine (260.27 mg, 2.57 mmol, 0.358 mL) were dissolved in methylene chloride (10.00 mL) and stirred at 50 ° C. for 16 hours. After completion of the reaction, the reaction solution was rotationally dried, diluted with water (50 mL), further extracted with methylene chloride (50 mL), and the organic phase was rotationally dried to obtain the target compound WX054-2.

Step 2: Synthesis of compound WX054-3 Compound WX054-2 (0.2 g, 547.04 μmol), compound BB-8 (0.188 g, 545.63 μmol), potassium acetate (0.215 g, 2.19 mmol), ferrocene palladium chloride (0.04 g,) 54.67 μmol) was dissolved in dioxane (5.00 mL) and water (1 mL), and the reaction solution was stirred at 100 ° C. for 1 hour under the protection of nitrogen gas. After completion of the reaction, the reaction solution was spin-dried, diluted with water (50 mL), extracted with methylene chloride (50 mL), and the organic phase was spin-dried. TLC (methylene chloride: methanol = 10: 1) showed that new points were generated. Separation was performed by column chromatography (methylene chloride: methanol = 1: 0-10: 1) to obtain the target compound WX054-3.

Step 3: Synthesis of Compounds WX054 and WX055 Compound WX054-3 is supercritical fluid chromatography (separation conditions [chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 35% -35%]) separated to obtain the enantiomers WX054 and WX055. The retention times were 4.179 min and 4.465 min, respectively, and the proportion was 1: 1. WX054: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.36 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 2.0 Hz, 1 H), 7.98 (s, 1 H), 7.75 --7.77 (m, 2 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.0 Hz, 1 H), 7.31 (dd, J = 8.0, 2.5 Hz, 1 H) , 6.97 --7.09 (m, 1 H), 4.02 (dd, J = 13.3, 4.8 Hz, 1 H), 3.80 (dd, J = 13.6, 10.0 Hz, 1 H), 2.64 --2.79 (m, 1 H) , 2.33 (tt, J = 7.3, 3.7 Hz, 1 H), 2.26 (s, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.35 --0.44 (m, 2 H), -0.03- 0.09 (m, 2 H) and WX055: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.37 (d, J = 2.0 Hz, 1 H), 8.10 (d, J = 2.5 Hz, 1 H), 7.98 (s, 1 H), 7.76 --7.88 (m, 2 H), 7.67 (d, J = 2.0 Hz, 1 H), 7.56 (d, J = 8.5 Hz, 1 H), 7.31 (dd, J = 8.5, 2.5 Hz, 1 H), 6.98 --7.07 (m, 1 H), 4.02 (dd, J = 13.6, 4.5 Hz, 1 H), 3.80 (dd, J = 13.6, 10.0 Hz, 1 H), 2.68 --2.78 (m, 1 H), 2.29 --2.42 (m, 1 H), 2.26 (s, 3 H), 1.01 (d, J = 7.0 Hz, 3 H), 0.39 (dd, J = 7.5, 2.0 Hz) , 2 H), -0.04 --0.10 (m, 2 H).

Example 35: WX056, WX057

Step 1: Synthesis of compound WX056-2 Add WX056-1 (168.09 mg, 1.93 mmol, 224.72 μL) and WX024-1 (200 mg, 642.82 μmol) to a pre-dried 40 mL flask and use DCM (2 mL). It was dissolved. This is followed by O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (366.63 mg, 964.22 μmol) and diisopropylethylamine (166.16 mg, 1.29 mmol). , 223.93 μL) was added. The reaction was stirred at 20 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and further purified by thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1). , WX056-2 was obtained.

Step 2: Synthesis of compound WX056-3 WX056-2 (209.54 mg, 473.34 μmol) and BB-3 (180 mg, 473.34 μmol) are added to a pre-dried 40 mL reaction bottle, followed by solvent 1,4-dioxane. (3 mL) and H ₂ O (0.3 mL) were added and dissolved, and potassium acetate (139.36 mg, 1.42 mmol) was further added. It was replaced with nitrogen gas, and [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (34.63 mg, 47.33 μmol) was added and replaced with nitrogen gas. The reaction was stirred at 90 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and further purified by preparative HPLC (method: chromatography column: Luna C18 100 * 30 mm 5 μm; Mobile phase: [water (0.1% TFA) -ACN]; B%: 40% -65%, 10 min), the target compound WX056-3 was obtained.

Step 3: Synthesis of compounds WX056 and WX057
WX056-3 is supercritical fluid chromatography (neutral) (chromatography column: Chiralpak AD-H 250 * 30mm id 5 μm; mobile phase: A: CO2, B: IPA (0.1% NH ₃ H ₂ O); gradient: Purification by B% = 45%; flow velocity: 70 g / min; wavelength: 220 nm; column temperature: 40 ° C.; back pressure: 100 bar) gave enantiomers WX056 and WX057. WX056: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (s, 1H), 8.21 --8.08 (m, 3H), 7.98 (d, J = 2.0 Hz, 1H), 7.91 --7.80 (m, 1H) , 7.80 --7.73 (m, 1H), 7.51 (br s, 1H), 7.18 --7.06 (m, 1H), 5.17 (br d, J = 9.3 Hz, 1H), 4.20 (dd, J = 4.7, 13.1 Hz) , 1H), 4.08 --3.99 (m, 1H), 3.98 (s, 3H), 3.72 (br d, J = 8.6 Hz, 1H), 3.02 --2.91 (m, 1H), 1.49 (br dd, J = 6.2) , 13.7 Hz, 1H), 1.38 --1.24 (m, 5H), 1.15 (tt, J = 7.4, 14.5 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H), 0.51 (t, J = 7.4 Hz) , 3H), m / z = 616.2 [M + 1], retention time was 3.05 min. WX057: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (s, 1H), 8.21 --8.08 (m, 3H), 7.98 (d, J = 2.0 Hz, 1H), 7.91 --7.80 (m, 1H) , 7.80 --7.73 (m, 1H), 7.51 (br s, 1H), 7.18 --7.06 (m, 1H), 5.17 (br d, J = 9.3 Hz, 1H), 4.20 (dd, J = 4.7, 13.1 Hz) , 1H), 4.08 --3.99 (m, 1H), 3.98 (s, 3H), 3.72 (br d, J = 8.6 Hz, 1H), 3.02 --2.91 (m, 1H), 1.49 (br dd, J = 6.2) , 13.7 Hz, 1H), 1.38 --1.24 (m, 5H), 1.15 (tt, J = 7.4, 14.5 Hz, 1H), 0.85 (t, J = 7.4 Hz, 3H), 0.51 (t, J = 7.4 Hz) , 3H), m / z = 616.2 [M + 1], retention time was 3.71 min. The proportion of WX056 and WX057 was about 1: 1.

Example 36: WX058, WX059

Step 1: Synthesis of Compound WX058-2 Add WX024-1 (0.25 g, 803.52 μmol) and WX058-1 (238.78 mg, 2.41 mmol, 189.51 μL) to a pre-dried 40 mL flask and methylene chloride (3 mL). Soluble in O- (7-azabenzotriazole-1-yl) -N, N, N', N'-tetramethyluronium hexafluorophosphate (458.28 mg, 1.21 mmol) and diisopropylethylamine (207.69). mg, 1.61 mmol, 279.91 μL) was added. The reaction was stirred at 20 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. Further purification was performed by a thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1) to obtain the target compound WX058-2, which was used as it was in the next step.

Step 2: Synthesis of compound WX058-3 WX058-2 (259.63 mg, 586.48 μmol) and BB-3 (230 mg, 586.48 μmol) are added to a pre-dried 40 mL reaction bottle, followed by solvent 1,4-dioxane. (3 mL) and water (0.3 mL) were added and dissolved, and potassium acetate (172.67 mg, 1.76 mmol) was further added. It was replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (42.91 mg, 58.65 μmol) was added, and further replaced with nitrogen gas. The reaction was stirred at 90 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and then further preparative HPLC (method: chromatography column: Luna C18 100 * 30 mm 5 μm; mobile phase: Purification with [water (0.1% TFA) -ACN]; B%: 45% -65%, 10 min) gave the target compound WX058-3.

Step 3: After synthetic separation of compounds WX058 and WX059, WX058-3 is supercritical fluid chromatography (neutral) (method: chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ Purification with H ₂ OEtOH]; B%: 35% -35%) gave enantiomers WX058 (retention time: 2.99 min) and WX059 (retention time: 3.27 min). WX058: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (s, 1H), 8.17 --8.10 (m, 2H), 8.08 (s, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.89 --7.82 (m, 1H), 7.81 --7.75 (m, 1H), 7.53 (br s, 1H), 7.16 --7.07 (m, 1H), 5.92 (br t, J = 6.5 Hz, 1H), 4.23 --4.13 (m, 1H), 4.11 --4.03 (m, 1H), 3.98 (s, 3H), 3.91 (br dd, J = 8.5, 15.5 Hz, 1H), 3.85 --3.73 (m, 1H), 3.15 --3.03 ( m, 1H), 1.33 (d, J = 6.8 Hz, 3H) .MS, m / z = 628.1 [M + 1]. WX059: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (s, 1H), 8.17 --8.10 (m, 2H), 8.08 (s, 1H), 7.98 (d, J = 1.8 Hz, 1H), 7.89 --7.82 (m, 1H), 7.81 --7.75 (m, 1H), 7.53 (br s, 1H), 7.16 --7.07 (m, 1H), 5.92 (br t, J = 6.5 Hz, 1H), 4.23 --4.13 (m, 1H), 4.11 --4.03 (m, 1H), 3.98 (s, 3H), 3.91 (br dd, J = 8.5, 15.5 Hz, 1H), 3.85 --3.73 (m, 1H), 3.15 --3.03 ( m, 1H), 1.33 (d, J = 6.8 Hz, 3H) .MS, m / z = 628.1 [M + 1].

Example 37: WX060, WX061

Step 1: Synthesis of compound WX060-1.
Raw materials WX024-1 (250 mg, 803.52 μmol), O- (7-azabenzotriazol-1-yl) -N, N, N', N'-tetramethyluronium hex in a pre-dried 40 mL reaction bottle Fluorophosphate (458.28 mg, 1.21 mmol) was added, dissolved in the solvent methylene chloride (3 mL), and the raw material ethylamine (108.68 mg, 2.41 mmol, 157.73 μL) was added, followed by N, N-diisopropylethylamine. (207.70 mg, 1.61 mmol, 279.92 μL) was added, and the mixture was stirred at 80 ° C. for 12 hours. Thin-layer chromatography detection (methylene chloride: methanol = 10: 1) showed that the raw material had disappeared and a new product had been produced. The reaction was quenched with 10 mL of water, extracted with methylene chloride (100 mL x 3), combined with the organic phases, the resulting organic phase was dried over anhydrous sodium sulfate and then concentrated under reduced pressure with a pump at 50 ° C. Purification by preparative TLC (methylene chloride: methanol = 15: 1) gave the target compound WX060-1. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.3 Hz, 1H), 8.10 (s, 1H), 7.84 (dd, J = 2.3, 8.6 Hz, 1H), 7.59 (d, J) = 8.7 Hz, 1H), 4.16 (dd, J = 4.9, 13.2 Hz, 1H), 3.99 (dd, J = 9.5, 13.2 Hz, 1H), 3.30 --3.26 (m, 1H), 3.22 --3.17 (m, 2H), 3.01 (s, 3H), 2.81 (s, 4H).

Step 2: Synthesis of compound WX060-2.

Raw materials WX060-1 (250 mg, 739.21 μmol), BB-3 (327.25 mg, 739.21 μmol) and potassium acetate (217.64 mg, 2.22 mmol) were added to a pre-dried 40 mL reaction bottle, and solvent 1,4- Dissolve in dioxane (3 mL), water (0.3 mL), replace with nitrogen gas, followed by [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (54.09 mg, 73.92 μmol) It was added, replaced with nitrogen gas, and further stirred at 80 ° C. for 3 hours. After completion of the reaction, the reaction was quenched with 10 mL of water, extracted with methylene chloride (10 mL × 3), the organic phases were combined, the obtained organic phase was dried over anhydrous sodium sulfate, and then reduced under reduced pressure with a pump at 50 ° C. To obtain the target compound WX060-2.

Step 3: Synthesis of compounds WX060 and WX061.

WX060-2 is SFC (chromatography column: AD (250 mm * 30 mm, 5 μμ); mobile phase: [A is CO2, B is IPA (0.1% NH ₃ H ₂ O)]; B%: 45% -45 % Flow velocity: 70 g / min: Wavelength: 220 nm; Column temperature: 40 ° C; System back pressure: 100 bar) Separated by enantiomer WX060 (holding time: 3.08 min) and WX061 (holding time: 3.31 min). Obtained. WX060: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 7.78 (s, 1H), 7.64 (d, J = 2.0 Hz, 1H), 7.62 (s, 1H), 7.54 (dd, J = 6.0, 8.8) Hz, 1H), 7.47 --7.41 (m, 2H), 7.20 (d, J = 8.4 Hz, 1H), 6.90 (dd, J = 2.3, 8.5 Hz, 1H), 6.68 (br t, J = 8.5 Hz, 1H), 3.69 (dd, J = 4.9, 13.5 Hz, 1H), 3.45 (dd, J = 9.9, 13.2 Hz, 1H), 3.31 (s, 3H), 2.60 --2.47 (m, 2H), 2.42 (s) , 1H), 0.68 (d, J = 7.1 Hz, 3H), 0.37 (t, J = 7.3 Hz, 3H). WX061: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.33 (s, 1H), 8.21 (s, 1H), 8.18 (s, 1H), 8.10 (dd, J = 6.0, 8.8 Hz, 1H), 8.03 --7.98 (m, 2H), 7.76 (d, J = 8.4 Hz, 1H), 7.46 (dd, J = 2.4, 8.4 Hz, 1H), 7.26 --7.21 (m, 1H), 4.29 --4.23 (m, 1H) ), 4.01 (dd, J = 10.0, 13.3 Hz, 1H), 3.87 (s, 3H), 3.16 --3.03 (m, 3H), 2.98 (s, 2H), 1.24 (d, J = 6.8 Hz, 3H) , 0.93 (t, J = 7.3 Hz, 3H).

Example 38: WX062, WX063

Step 1: Synthesis of compound WX062-4 Add raw material WX024-1 (5 g, 16.07 mmol), raw material methylamine (598.92 mg, 19.28 mmol) and solvent methylene chloride (50 mL) to a pre-dried 500 mL bite flask. And then 2,4,6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (12.27 g, 19.28 mmol, 11.47 mL, 50% purity) ), N, N-diisopropylethylamine (6.23 g, 48.21 mmol, 8.40 mL) was added, and the mixture was further stirred at 25 ° C. for 12 hours. After detecting the end of the reaction by thin layer chromatography (methylene chloride: methanol = 10: 1), water (50 mL) was added to the reaction system, the reaction was quenched, and the mixture was further extracted with methylene chloride (50 mL × 3). , Organic phases are combined, and the obtained organic phase is dried over anhydrous sodium sulfate, dried at 45 ° C. under reduced pressure with a pump, and subjected to column chromatography (petroleum ether: ethyl acetate = 1: 0 to 0: 1). The mixture was separated and purified to obtain the target compound WX062-4. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.40 (br s, 1H), 8.11 (s, 1H), 7.84 (br d, J = 8.8 Hz, 1H), 7.80 --7.76 (m, 1H), 7.80 --7.76 (m, 1H), 7.60 (d, J = 8.5 Hz, 1H), 4.20 --4.10 (m, 2H), 4.02 (dd, J = 9.5, 13.2 Hz, 2H), 2.95 --2.89 (m, 1H) ), 2.74 (d, J = 4.8 Hz, 4H), 2.73 --2.72 (m, 1H), 1.28 (d, J = 7.0 Hz, 4H).

Step 2: Synthesis of compound WX062-3 Raw material WX062-1 (525 mg, 1.03 mmol) and raw material WX062-2 (261.46 mg, 1.03 mmol) are added to a pre-dried 15 mL reaction bottle, and solvent 1,4 dioxane ( Dissolve in 5 mL), then add potassium acetate (202.10 mg, 2.06 mmol), replace with nitrogen gas and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (75.34 mg). , 102.96 μmol) was added, replaced with nitrogen gas, and further stirred at 110 ° C. for 3 hours. After completion of the reaction, the target compound WX062-3 was obtained without post-treatment and used as it was in the next reaction.

Step 3: Synthesis of compound WX062-5 Raw material WX062-4 (300 mg, 925.43 μmol) and raw material WX062-3 (566.97 mg, 1.02 mmol) are added to a pre-dried 15 mL reaction bottle, and solvent 1,4-dioxane is added. Dissolve in (3 mL), water (0.3 mL), then add potassium acetate (181.65 mg, 1.85 mmol), replace with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) Dichloride (67.71 mg, 92.54 μmol) was added, replaced with nitrogen gas, and further stirred at 90 ° C. for 12 hours. The reaction termination was detected by thin layer chromatography (methylene chloride: methanol = 10: 1). Water (10 mL) was added to the reaction system, the organic phase was further extracted with methylene chloride (10 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure with a pump, and further divided. Purification with Tori TLC (methylene chloride: methanol = 15: 1) gave the target compound WX062-5.

Step 4: Synthesis of compounds WX062 and WX063.

WX062-5 is SFC (chromatography column: ChiralcelOD-H 250 * 30mm id 5 μm; mobile phase: A: CO ₂ , B: MeOH (0.1% NH ₃ H ₂ O); gradient: B% = 45%; flow velocity Enantiomers WX062 (holding time: 1.460 min) and WX063 (holding time: 1.453 min) were obtained by separation by: 70 g / min; wavelength: 220 nm; column temperature: 40 ° C.; back pressure: 100 bar). WX062: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.44 (s, 1H), 8.25 (s, 1H), 8.19 --8.14 (m, 2H), 7.98 (s, 1H), 7.82 --7.74 (m, 2H), 7.30 (dd, J = 2.3, 8.0 Hz, 1H), 7.21 --7.14 (m, 1H), 5.80 (br d, J = 4.4 Hz, 1H), 4.91 (br s, 2H), 4.20 (dd , J = 4.6, 13.2 Hz, 1H), 4.05 --4.05 (m, 1H), 4.06 (dd, J = 9.6, 13.4 Hz, 1H), 2.98 (br d, J = 9.3 Hz, 1H), 2.75 (d) , J = 4.8 Hz, 3H), 1.65 (br s, 1H), 1.31 (d, J = 6.9 Hz, 3H). WX063: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.44 (br s, 1H), 8.26 (br s, 1H), 8.20 --8.13 (m, 2H), 7.98 (s, 1H), 7.83 --7.74 ( m, 2H), 7.30 (br d, J = 8.3 Hz, 1H), 7.17 (br t, J = 7.2 Hz, 1H), 5.79 --5.79 (m, 1H), 4.91 (br s, 2H), 4.23- 4.15 (m, 1H), 4.11 --4.10 (m, 1H), 4.06 --4.06 (m, 1H), 4.11 --3.99 (m, 1H), 2.98 (br d, J = 8.8 Hz, 1H), 2.75 (br d, J = 4.5 Hz, 3H), 1.31 (br d, J = 6.8 Hz, 3H).

Example 39: WX064, WX065

Step 1: Synthesis of compound WX064-1 Add BB-2 (1.5 g, 4.42 mmol), BB-3 (2.35 g, 5.31 mmol) and potassium carbonate (1.30 g, 13.27 mmol) to a pre-dried 100 mL bite flask. Then, it was dissolved in 1,4-dioxane (15 mL) and water (2 mL), replaced with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II). (323.59 mg, 442.24 μmol) was added and further replaced with nitrogen gas. The reaction was stirred at 90 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, and after separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and separated by column chromatography (petroleum ether: ethyl acetate = 30: 1, 1: 1). Then, it was purified to obtain WX064-1. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.26 (d, J = 2.0 Hz, 1H), 8.11 --8.01 (m, 3H), 7.90 (d, J = 2.3 Hz, 1H), 7.81 --7.74 (m) , 1H), 7.73 --7.76 (m, 1H), 7.47 (s, 1H), 7.20 --7.15 (m, 1H), 7.10 --7.00 (m, 1H), 4.17 --3.95 (m, 4H), 3.91 (s) , 3H), 3.19 --3.03 (m, 1H), 1.25 (d, J = 7.3 Hz, 3H), 1.13 (t, J = 7.2 Hz, 3H).

Step 2: Synthesis of compound WX064-2 WX064-1 (1.30 g, 2.26 mmol) is added to a pre-dried 40 mL reaction vessel, then dissolved in tetrahydrofuran (10 mL) and finally lithium hydroxide monohydrate. A solution of compound (271.30 mg, 6.78 mmol) in water (10 mL) was added. The reaction mixture was stirred at 0 ° C. for 1 hour. After completion of the reaction, add 10 mL water / 10 mL ethyl acetate to the reaction system to dilute, separate the liquids, collect the aqueous phase, adjust the aqueous phase to PH = 3 with 1N hydrochloric acid, and ethyl acetate (5 mL). Extracted in × 3), the organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give WX064-2. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.31 (s, 2H), 8.21 (d, J = 2.0 Hz, 1H), 8.08 (dd, J = 6.0, 8.8 Hz, 1H), 8.02 --7.96 (m) , 2H), 7.75 (d, J = 8.6 Hz, 1H), 7.44 (br d, J = 8.6 Hz, 1H), 7.21 (br t, J = 8.6 Hz, 1H), 4.21 --4.15 (m, 2H) , 3.85 (s, 3H), 3.11 (br d, J = 6.4 Hz, 1H), 1.27 (d, J = 7.3 Hz, 3H).

Step 3: Synthesis of compound WX064-4.

Add raw material WX064-2 (146 mg, 266.93 μmol), raw material WX064-3 (24.06 mg, 320.32 μmol, 27.85 μL) and solvent methylene chloride (2 mL) to a pre-dried reaction bottle, followed by 2,4. , 6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (203.84 mg, 320.32 μmol, 190.50 μL, 50% purity) was added to the system. Was cooled to 0 ° C., N, N-diisopropylethylamine (103.50 mg, 800.80 μmol, 139.48 μL) was slowly added, and the reaction solution was stirred at 25 ° C. for 12 hours. The reaction termination was detected by thin layer chromatography (methylene chloride: methanol = 10: 1). Water (10 mL) was added to the reaction solution, and methylene chloride (10 mL × 3) was further added to extract the organic phase. The obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure with a pump. Further, purification was performed by preparative TLC (methylene chloride: methanol = 15: 1) to obtain the target compound WX064-4.

Step 4: Synthesis of compounds WX064 and WX065.

WX064-4 is SFC (chromatography column: Chiralcel OJ-H 250 * 30mm id 5μm; mobile phase: A: CO2, B: MeOH; gradient: B% = 30%; flow velocity: 60 g / min; wavelength: 220 nm Separation by column temperature: 40 degrees; back pressure: 100 bar) gave enantiomers WX064 (holding time: 1.846 min) and WX065 (holding time: 2.85 min). WX064: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (s, 1H), 8.15 --8.15 (m, 1H), 8.15 --8.11 (m, 2H), 8.10 (s, 1H), 7.97 (d, J = 2.0 Hz, 1H), 7.85 --7.79 (m, 1H), 7.79 --7.74 (m, 1H), 7.25 (d, J = 2.2 Hz, 1H), 7.15 --7.07 (m, 1H), 5.99 (br s, 1H), 4.27 --4.15 (m, 1H), 4.04 --3.99 (m, 1H), 3.97 (s, 3H), 3.46 --3.37 (m, 1H), 3.37 --3.27 (m, 2H), 3.26- 3.19 (m, 1H), 3.12 (s, 3H), 3.02 --2.93 (m, 1H), 1.33 --1.33 (m, 1H), 1.29 (d, J = 7.1 Hz, 2H), 1.30 --1.22 (m, 1H). WX065: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.34 (br s, 1H), 8.12 (br d, J = 13.2 Hz, 3H), 7.99 (s, 1H), 7.87 --7.81 (m, 1H) , 7.81 --7.74 (m, 1H), 7.13 (br s, 1H), 5.87 (br s, 1H), 4.27 --4.17 (m, 1H), 4.04 (s, 1H), 3.99 (s, 3H), 3.40 (br s, 1H), 3.35 (br s, 2H), 3.24 (br d, J = 9.3 Hz, 1H), 3.13 (s, 3H), 2.98 (br s, 1H), 1.30 (br d, J = 6.8 Hz, 3H), 1.27 --1.23 (m, 1H), 1.15 (br s, 1H).

Example 40: WX066, WX067

Step 1: Synthesis of compound WX066-2.

Raw material WX064-2 (120 mg, 219.40 μmol), raw material WX066-1 (26.21 mg, 263.28 μmol, HCl) and solvent methylene chloride (2 mL) were added to a pre-dried reaction bottle, followed by 2,4, Add 6-tripropyl-1,3,5,2,4,6-trioxatriphosphorinane 2,4,6-trioxide (167.54 mg, 263.28 μmol, 156.58 μL, 50% purity) to 0 system. The temperature was lowered to ° C., N, N-diisopropylethylamine (113.42 mg, 877.59 μmol, 152.86 μL) was slowly added, and the reaction solution was stirred at 25 ° C. for 12 hours. The reaction termination was detected by thin layer chromatography (methylene chloride: methanol = 10: 1). Water (10 mL) was added to the reaction solution, the organic phase was further extracted with methylene chloride (10 mL * 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then dried under reduced pressure by a pump, and further ( Purification with methylene chloride: methanol = 15: 1) gave the target compound WX066-2.

Step 2: Synthesis of compounds WX066 and WX067.

WX066-2 is SFC (chromatography column: Chiralcel OJ-H 250 * 30mm id 5μm; mobile phase: A: CO ₂ , B: MeOH; gradient: B% = 35%; flow velocity: 60 g / min; wavelength: 220 Separation was performed by nm; column temperature: 40 ° C.; back pressure: 100 bar) to obtain enantiomers WX066 (holding time: 1.907 min) and WX067 (holding time: 1.916 min). WX066: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.27 (d, J = 1.8 Hz, 1H), 8.16 --8.12 (m, 1H), 8.11 --8.09 (m, 2H), 7.96 (d, J = 2.2 Hz, 1H), 7.84 --7.80 (m, 1H), 7.77 --7.73 (m, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.15 --7.07 (m, 1H), 6.13 (br t, br t, J = 5.6 Hz, 1H), 4.50 --4.38 (m, 1H), 4.37 --4.26 (m, 1H), 4.21 (dd, J = 5.0, 13.3 Hz, 1H), 4.03 (dd, J = 9.5, 13.2 Hz , 1H), 3.98 (s, 3H), 3.54 (q, J = 5.1 Hz, 1H), 3.47 (q, J = 5.1 Hz, 1H), 3.08 --2.99 (m, 1H), 1.31 (d, J = 7.1 Hz, 3H). WX067: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (d, J = 1.8 Hz, 1H), 8.17 --8.13 (m, 2H), 8.10 (s, 1H), 7.98 (d, J = 2.2 Hz) , 1H), 7.86 --7.82 (m, 1H), 7.80 --7.76 (m, 1H), 7.54 (s, 1H), 7.28 (br s, 1H), 7.27 --7.25 (m, 1H), 7.26 (d, J = 2.4 Hz, 1H), 7.16 --7.10 (m, 1H), 5.96 (br s, 1H), 4.50 --4.37 (m, 1H), 4.37 --4.25 (m, 1H), 4.21 (dd, J = 5.1 , 13.2 Hz, 1H), 4.04 (dd, J = 9.6, 13.1 Hz, 1H), 3.99 (s, 3H), 3.54 (q, J = 5.1 Hz, 1H), 3.50 --3.44 (m, 1H), 3.06 --2.96 (m, 1H), 1.32 (d, J = 7.1 Hz, 3H).

Example 41: WX068, WX069

Step 1: Synthesis of compound WX068-2
Dissolve BB-2 (209.26 mg, 616.95 μmol) in dioxane (5.00 mL) and water (1.00 mL), to which WX068-1 (185.16 mg, 740.35 μmol), [1,1'-bis (diphenylphosphino) ) Ferrocene] Dichloropalladium (II) methylene chloride complex (100.77 mg, 123.39 μmol) and potassium acetate (242.19 mg, 2.47 mmol) were added, and the reaction solution was stirred at 100 ° C. for 3 hours under nitrogen gas protection to complete the reaction. Then, the reaction solution was rotationally dried, and the compound was separated by preparative HPLC to obtain the target compound WX068-2.

Step 2: Synthesis of compound WX068-4
WX068-2 (0.49 g, 1.28 mmol) was dissolved in pyridine (4.00 mL), WX068-3 (298.06 mg, 1.41 mmol) was added thereto, and the reaction solution was stirred at 25 ° C. for 10 hours. , The reaction solution was spin-dried to obtain the target compound WX068-4.

Step 3: Synthesis of compound WX068-5
Dissolve WX068-4 (0.5 g, 896.63 μmol) in methylamine solution (2 M, 50 mL), stir the reaction solution at 80 ° C. for 10 hours, and after completion of the reaction, spin-dry the reaction solution to separate the compounds. Separation was performed by taking HPLC to obtain the target compound WX068-5.

Step 4: Synthesis of compounds WX068 and WX069
WX068-5 is separated by SFC (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm), elution condition: 0.1% NH ₃ H ₂ OEtOH, B%: 55% -55%, flow rate: 80 mL / min). Purification was performed to obtain enantiomers WX068 (Rt = 0.732 min) and WX069 (Rt = 2.220 min). WX068: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.40 (d, J = 2Hz, 1H), 8.22 (d, J = 2Hz, 1H), 8.13 (s, 1H), 8.09 (d, J = 2.4) Hz, 1H), 7.89 (d, J = 2.4Hz, 1H), 7.80-7.82 (m, 1H), 7.14 (m, 1H), 5.56 (s, 1H), 4.17-4.21 (m, 1H), 4.03 -4.08 (m, 1H), 3.97 (s, 3H), 2.93-2.99 (m, 1H), 2.76 (s, 3H), 2.64 (s, 3H), 1.29 (d, J = 6.8Hz, 1H). WX069: ¹ H NMR (400 MHz, CHLOROFORM-d) δ = 8.32 (d, J = 2.0 Hz, 1 H), 8.14 (d, J = 2.3 Hz, 1 H), 8.05 (s, 1 H), 8.01 (d, J = 2.3 Hz, 1 H), 7.82 (dd, J = 8.4, 2.1 Hz, 1 H), 7.71 --7.76 (m, 1 H), 7.19 (s, 1 H), 6.93 --7.17 (m) , 1 H), 5.54 (br d, J = 4.5 Hz, 1 H), 4.11 (dd, J = 13.2, 4.9 Hz, 1 H), 3.98 (dd, J = 13.2, 9.4 Hz, 1 H), 3.89 (s, 3 H), 2.84 --2.94 (m, 1 H), 2.67 (d, J = 4.8 Hz, 3 H), 2.56 (s, 3 H), 2.49 (s, 3 H), 1.22 (d, J = 7.0 Hz, 3 H).

Example 42: WX070, WX071

Step 1: Synthesis of compound WX070-2 Compound WX070-1 (5.0 g, 21.64 mmol), bis (pinacolato) diboron (5.50 g, 21.64 mmol), potassium acetate (4.25 g, 43.28 mmol) to dioxane (10 mL) After dissolution, Pd (dppf) Cl2 (353.45 mg, 432.81 μmol) was added, and the mixture was heated to 100 ° C. under the protection of nitrogen gas and stirred for 5 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (50 mL), and extracted with methylene chloride (50 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure and separated by a chromatography column (eluent: methanol / methylene chloride = 0% -5%) to obtain the target compound WX070-2. ^{1 1} H NMR (400MHz, Methanol-d4) δ: 9.03 --8.74 (m, 1H), 8.57 --8.39 (m, 1H), 3.17 --2.97 (m, 2H), 1.49 --1.31 (m, 15H). MS-ESI m / z: 197.1 [M + H] ⁺ .

Step 2: Synthesis of compound WX070-3 Compound WX070-2 (0.5 g, 1.80 mmol), BB-2 (610.53 mg, 1.80 mmol), potassium acetate (706.61 mg, 7.20 mmol) in dioxane (2 mL) and water (2 mL) It was dissolved in 0.2 mL), after which Pd (dppf) Cl ₂ (153.34 mg, 187.77 μmol) was added, and the mixture was heated to 100 ° C. under the protection of nitrogen gas and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (50 mL), and extracted with methylene chloride (50 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, and the residue was separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1:20) to obtain the target compound WX070-3. MS-ESI m / z: 411.0 [M + H] ⁺ , 413.0 [M + H + 2] ⁺ .

Step 3: Synthesis of Compound WX070-4 Compound WX070-3 (0.5 g, 1.22 mmol) is dissolved in methanol (30 mL) followed by ammonium chloride (651.66 mg, 12.18 mmol) and zinc powder (398.31 mg, 6.09 mmol). ) Was added, and the mixture was stirred at 20 ° C. for 2 hours. After completion of the reaction, the mixture was filtered, the mother liquor was collected, the organic solvent was spin-dried, poured into water (50 mL), and extracted with methylene chloride (50 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX070-4, which was used as it was in the next step. MS-ESI m / z: 381.0 [M + H] ⁺ , 383.0 [M + H + 2] ⁺ .

Step 4: Synthesis of Compound WX070-5 Compound WX070-4 (300 mg, 788.56 μmol) is dissolved in pyridine (3 mL) and 2-chloro-4-fluorobenzenesulfonyl chloride (270.94 mg, 1.18 mmol) at 0 ° C. Was added, and the mixture was stirred at 20 ° C. for 2 hours. After completion of the reaction, the organic solvent was spin-dried, poured into water (10 mL), and extracted with methylene chloride (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1:20), and further separated by an HPLC preparative column. The target compound WX070-5 was obtained. MS-ESI m / z: 573.1 [M + H] ⁺ , 575.1 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX070-6
WX070-5 (0.3 g, 523.53 μmol) was dissolved in a methylamine alcohol solution (20 mL), heated to 80 ° C. and stirred for 3 hours. After completion of the reaction, the mixture is cooled to room temperature, the solvent is removed under reduced pressure, separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1: 15), and further separated by an HPLC preparative column (water s Xbridge 150 *). 25 5u; Mobile phase: [Water (10 mM NH ₄ HCO ₃ ) -ACN]; B%: 15% -45%, 8 min) to obtain the target compound WX070-6.

Step 6: Synthesis of Compounds WX070 and WX071 Compound WX070-6 is supercritical fluid chromatography (separation condition column: C2 250 mm * 30 mm, 10 μm; mobile phase: [0.1% NH ₃ H ₂ OMeOH]; B%: 55%- 55%) to give enantiomers WX070 and WX071. The retention times were 4.997 min and 7.676 min, respectively, and the proportion was 1: 1. WX070: ¹ H NMR (400MHz, Methanol-d ₄ ) δ: 8.56 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 8.04 --7.82 ( m, 2H), 7.80 --7.59 (m, 2H), 7.45 (dd, J = 2.4, 8.4 Hz, 1H), 7.15 (dt, J = 2.5, 8.4 Hz, 1H), 4.14 (dd, J = 4.8, 13.3 Hz, 1H), 3.93 (dd, J = 9.8, 13.3 Hz, 1H), 2.99 --2.81 (m, 1H), 2.76 (q, J = 7.5 Hz, 2H), 2.64 --2.42 (m, 3H), 1.14 (d, J = 7.0 Hz, 3H), 1.04 (t, J = 7.5 Hz, 3H). MS-ESI m / z: 558.1 [M + H] ⁺ , 560.1 [M + H + 2] ⁺ . WX071: ¹ H NMR (400MHz, Methanol-d ₄ ) δ: 8.52 (d, J = 2.0 Hz, 1H), 8.23 (d, J = 2.0 Hz, 1H), 8.10 (s, 1H), 8.00 --7.83 ( m, 2H), 7.75 (d, J = 2.0 Hz, 1H), 7.68 (d, J = 8.5 Hz, 1H), 7.43 (dd, J = 2.5, 8.3 Hz, 1H), 7.15 (dt, J = 2.5) , 8.4 Hz, 1H), 4.14 (dd, J = 4.9, 13.4 Hz, 1H), 3.93 (dd, J = 9.9, 13.4 Hz, 1H), 3.51 (q, J = 7.0 Hz, 2H), 2.93 --2.84 (m, 1H), 2.96 --2.82 (m, 1H), 2.76 (q, J = 7.5 Hz, 2H), 2.52 (s, 3H), 1.18 --1.11 (m, 3H), 1.09 --1.05 (m, 3H) ). MS-ESI m / z: 558.1 [M + H] ⁺ , 560.1 [M + H + 2] ⁺ .

Example 43: WX072, WX073

Step 1: Synthesis of compound WX072-2 WX064-2 (150 mg, 274.25 μmol) was added to a pre-dried 40 mL reaction bottle and then dissolved in methylene chloride (5 mL). Then, at 0 ° C., WX072-1 (40.11 mg, 548.49 μmol, 54.50 μL) and 1-propanephosphonic anhydride (cyclic trimmer) (261.78 mg, 411.37 μmol, 244.65 μL, 50% purity) were added, and finally. Diisopropylethylamine (70.89 mg, 548.49 μmol, 95.54 μL) was added. The reaction was stirred at 20 ° C. for 16 hours. After completion of the reaction, directly spin-dry and preparative HPLC method (chromatography column: Luna C18 100 * 30 5 μ; mobile phase: [water (0.1% TFA) -ACN]; B%: 50% -80%, 10 min ) To obtain WX072-2.

Step 2: Synthesis of compounds WX072 and WX073
WX072-2 is supercritical fluid chromatography (separation method: chromatography column: Chiralpak AD-H 250 * 30mm id 5 μm; mobile phase: A: CO ₂ , B: IPA (0.1% NH ₃ H ₂ O); gradient: B% = 42%; Flow velocity: 70 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by enantiomer WX072 (holding time: 2.97 min) and WX073 (holding time:: 3.28 min) was obtained. WX072: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.21 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 8.07 (s, 1H), 8.00 (dd, J) = 5.9, 8.9 Hz, 1H), 7.93 --7.85 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 2.5, 8.5 Hz, 1H), 7.19 --7.08 (m, 1H), 4.16 (dd, J = 4.8, 13.3 Hz, 1H), 3.97 --3.84 (m, 1H), 3.05 --2.94 (m, 1H), 2.89 (dd, J = 6.7, 13.2 Hz, 1H), 2.66 (dd, J = 7.2, 13.2 Hz, 1H), 1.46 (quind, J = 6.8, 13.6 Hz, 1H), 1.15 (d, J = 7.0 Hz, 3H), 0.59 (d, J = 6.7 Hz, 3H) , 0.54 (d, J = 6.8 Hz, 3H). MS, m / z = 602.2 [M + 1]. WX073: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.21 (d, J = 2.1 Hz, 1H), 8.10 (d, J = 2.3 Hz, 1H), 8.07 (s, 1H), 8.00 (dd, J) = 5.9, 8.9 Hz, 1H), 7.93 --7.85 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.37 (dd, J = 2.5, 8.5 Hz, 1H), 7.19 --7.08 (m, 1H), 4.16 (dd, J = 4.8, 13.3 Hz, 1H), 3.97 --3.84 (m, 1H), 3.05 --2.94 (m, 1H), 2.89 (dd, J = 6.7, 13.2 Hz, 1H), 2.66 (dd, J = 7.2, 13.2 Hz, 1H), 1.46 (quind, J = 6.8, 13.6 Hz, 1H), 1.15 (d, J = 7.0 Hz, 3H), 0.59 (d, J = 6.7 Hz, 3H) , 0.54 (d, J = 6.8 Hz, 3H). MS, m / z = 602.2 [M + 1]. The proportion of isomers WX072 and WX073 was about 1: 1.

Example 44: WX074, WX075

Step 1: Synthesis of compound WX074-2 WX074-1 (39.01 mg, 548.50 μmol, 47.00 μL) was added to a pre-dried 40 mL reaction bottle and then dissolved in methylene chloride (5 mL). Then WX064-2 (150 mg, 274.25 μmol) and 1-propanephosphonic anhydride (cyclic trimmer) (261.78 mg, 411.38 μmol, 244.65 μL, 50% purity) were added, and finally diisopropylethylamine (diisopropylethylamine) at 0 ° C. 70.89 mg, 548.50 μmol, 95.54 μL) was added. The reaction was stirred at 20 ° C. for 2 hours. After completion of the reaction, directly spin-dry and preparative HPLC (method: chromatography column: Luna C18 100 * 30mm 5 μm; mobile phase: [water (0.1% TFA) -ACN]; B%: 45% -65%, It was separated and purified by 10 min) to obtain WX074-2.

Step 2: Synthesis of compounds WX074 and WX075
WX074-2 is supercritical fluid chromatography (method: chromatography column: Chiralpak AD-H 250 * 30mm id 5 μm; mobile phase: A: CO2, B: IPA (0.1% NH ₃ H ₂ O); gradient: B % = 42%; Flow velocity: 70 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by enantiomer WX074 (holding time: 3.21 min) and WX075 (holding time: 3.46) min) was obtained. WX074: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.25 (d, J = 2.0 Hz, 1H), 8.12-8.03 (m, 2H), 8.01 (s, 1H), 7.91 (d, J = 2.3 Hz) , 1H), 7.80 --7.74 (m, 1H), 7.73 --7.77 (m, 1H), 7.47 (s, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.09 --6.98 (m, 1H), 5.58 (br d, J = 8.0 Hz, 1H), 4.32 --4.18 (m, 1H), 4.10 (dd, J = 5.0, 13.2 Hz, 1H), 3.98 --3.85 (m, 4H), 2.91 --2.67 (m) , 1H), 2.30 --2.16 (m, 1H), 2.15 --2.03 (m, 1H), 1.77 --1.62 (m, 1H), 1.54 --1.50 (m, 3H), 1.20 (d, J = 7.0 Hz, 3H) ). MS, m / z = 600.2 [M + 1]. WX075: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.25 (d, J = 2.0 Hz, 1H), 8.12-8.03 (m, 2H), 8.01 (s, 1H), 7.91 (d, J = 2.3 Hz) , 1H), 7.80 --7.74 (m, 1H), 7.73 --7.77 (m, 1H), 7.47 (s, 1H), 7.21 (d, J = 2.5 Hz, 1H), 7.09 --6.98 (m, 1H), 5.58 (br d, J = 8.0 Hz, 1H), 4.32 --4.18 (m, 1H), 4.10 (dd, J = 5.0, 13.2 Hz, 1H), 3.98 --3.85 (m, 4H), 2.91 --2.67 (m) , 1H), 2.30 --2.16 (m, 1H), 2.15 --2.03 (m, 1H), 1.77 --1.62 (m, 1H), 1.54 --1.50 (m, 3H), 1.20 (d, J = 7.0 Hz, 3H) ). MS, m / z = 600.2 [M + 1]. The proportion of isomers WX074 and WX075 was about 1: 1.

Example 45: WX076, WX077

Step 1: Synthesis of compound WX076-2 WX076-1 (31.32 mg, 548.50 μmol, 38.01 μL) was added to a pre-dried 40 mL reaction bottle and then dissolved in methylene chloride (5 mL). Then WX064-2 (150 mg, 274.25 μmol) and 1-propanephosphonic anhydride (cyclic trimmer) (261.78 mg, 411.38 μmol, 244.65 μL, 50% purity) were added, and finally diisopropylethylamine (diisopropylethylamine) at 0 ° C. 70.89 mg, 548.50 μmol, 95.54 μL) was added dropwise. The reaction was stirred at 20 ° C. for 2 hours. After completion of the reaction, directly spin-dry and preparative HPLC (method: chromatography column: Luna C18 100 * 30mm 5 μm; mobile phase: [water (0.1% TFA) -ACN]; B%: 40% -80%, It was separated and purified by 10 min) to obtain WX076-2.

Step 2: Synthesis of compounds WX076 and WX077 Compound WX076-2 (130 mg) is supercritical fluid chromatography (chromatography column: Chiralpak AD-H 250 * 30 mm id 5 μm; mobile phase: A: CO2, B: MeOH (0.1%) NH ₃ H ₂ O); Gradient: B% = 42%; Flow velocity: 70 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by enantiomer WX076 (holding time: 3.04) min) and WX077 (holding time: 5.63 min) were obtained. WX076: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.10 (d, J = 2.1 Hz, 1H), 7.99 (d, J = 2.1 Hz, 1H), 7.97 (s, 1H), 7.88 (dd, J = 5.8, 8.9 Hz, 1H), 7.83 --7.76 (m, 2H), 7.55 (d, J = 8.4 Hz, 1H), 7.25 (dd, J = 2.6, 8.5 Hz, 1H), 7.02 (ddd, J = 2.6, 7.9, 8.8 Hz, 1H), 4.02 (dd, J = 4.8, 13.4 Hz, 1H), 3.79 (dd, J = 10.0, 13.4 Hz, 1H), 3.65 (s, 3H), 2.78 --2.65 (m) , 1H), 2.33 (tt, J = 3.8, 7.3 Hz, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.39 (dd, J = 1.7, 7.2 Hz, 2H), 0.08 --- 0.02 (m) , 2H). MS, m / z = 586.1 [M + 1]. WX077: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.10 (d, J = 2.0 Hz, 1H), 7.97 (s, 2H), 7.89 (dd, J = 5.8, 8.8 Hz, 1H), 7.80 (dd , J = 2.1, 8.5 Hz, 1H), 7.75 (br s, 1H), 7.55 (d, J = 8.4 Hz, 1H), 7.24 (dd, J = 2.4, 8.5 Hz, 1H), 7.06 --6.95 (m) , 1H), 4.02 (dd, J = 4.8, 13.4 Hz, 1H), 3.79 (dd, J = 10.0, 13.3 Hz, 1H), 3.66 (s, 3H), 2.76 --2.65 (m, 1H), 2.33 ( tt, J = 3.8, 7.3 Hz, 1H), 1.01 (d, J = 6.9 Hz, 3H), 0.42 --0.35 (m, 2H), 0.08 --- 0.03 (m, 2H). MS, m / z = 586.1 [M + 1]. The proportion of isomers WX076 and WX077 was about 1: 1.

Example 46: WX078, WX079

Step 1: Synthesis of compound WX078-2.

Compound WX064-2 (0.15 g, 274.25 μmol), compound WX078-1 (32.42 mg, 548.49 μmol, 47.12 μL), 1-propanephosphonic anhydride (cyclic trimmer) solution (209.42 mg,) in a pre-dried reaction bottle. 329.09 μmol, 195.72 μL, 50% purity) and methylene chloride (2 mL) were added in that order, and finally N, N-diethylpropylamine (70.89 mg, 548.49 μmol, 95.54 μL) was added. It was then replaced with nitrogen gas and stirred at 15 ° C. for 2 hours. After completion of the reaction, the reaction solution is distilled under reduced pressure to remove the solvent, and preparative HPLC (purification method: chromatography column: Agela Dμrashell C18 150 * 25mm 5μm; mobile phase: [water (10mM NH4HCO3) -ACN]; B%: 24% -54%, 10.5 min) was separated and purified to give compound WX078-2. ¹ H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J = 5.8) , 8.9 Hz, 1H), 8.04 --7.98 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 2.6, 8.5 Hz, 1H), 7.28 --7.20 (m, 1H) , 4.26 (dd, J = 4.8, 13.3 Hz, 1H), 3.99 (dd, J = 10.3, 13.2 Hz, 1H), 3.92 --3.83 (m, 4H), 3.02 --2.91 (m, 1H), 1.23 (d) , J = 6.9 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H).

Step 2: Synthesis of compounds WX078 and WX079.

Compound WX078-2 is a preparative SFC for supercritical fluid chromatography (chromatography column: Chiralpak AD-H 250 * 30 mm id 5 μm; mobile phase: A: CO2, B: EtOH (0.1% NH ₃ H ₂ O); gradient : B% = 42%; Flow velocity: 70 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by enantiomer WX078 (holding time: 3.40 min) and WX079 (holding time:: 3.96 min) was obtained. WX078: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.04 --7.98 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 2.6, 8.5 Hz, 1H), 7.28 --7.20 (m, 1H), 4.26 (dd, J = 4.8, 13.3 Hz, 1H), 3.99 (dd, J = 10.3, 13.2 Hz, 1H), 3.92 --3.83 (m, 4H), 3.02 --2.91 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H). WX079: ¹ H NMR (400MHz, METHANOL-d4) Shift = 8.34 (d, J = 2.1 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.17 (s, 1H), 8.10 (dd, J) = 5.8, 8.9 Hz, 1H), 8.04 --7.98 (m, 2H), 7.76 (d, J = 8.5 Hz, 1H), 7.47 (dd, J = 2.6, 8.5 Hz, 1H), 7.28 --7.20 (m, 1H), 4.26 (dd, J = 4.8, 13.3 Hz, 1H), 3.99 (dd, J = 10.3, 13.2 Hz, 1H), 3.92 --3.83 (m, 4H), 3.02 --2.91 (m, 1H), 1.23 (d, J = 6.9 Hz, 3H), 1.04 (d, J = 6.5 Hz, 3H), 0.85 (d, J = 6.7 Hz, 3H).

Example 47: WX080, WX081

Step 1: Synthesis of compound WX080-2.

Raw materials WX024-1 (1.5 g, 4.82 mmol) and WX080-1 (353.39 mg, 5.79 mmol, 349.89 μL) were added to a pre-dried 40 mL reaction bottle, dissolved in the solvent methylene chloride (15 mL), and nitrogen gas. Substitute with propylphosphonic acid anhydride (cyclic trimmer) (3.68 g, 5.79 mmol, 3.44 mL, 50% purity), N, N-diisopropylethylamine (1.87 g, 14.46 mmol, 2.52 mL). ) Was added slowly, and the mixture was stirred at 25 ° C. for 12 hours. The reaction termination was detected by thin layer chromatography (methylene chloride: methanol = 10: 1). Water (10 mL) was added to the reaction mixture, and the mixture was further extracted with methylene chloride (10 mL × 3). The obtained organic phase was dried over anhydrous sodium sulfate, dried at 35 ° C. under reduced pressure with a pump, and column chromatographed. The target compound WX080-2 was obtained by separation and purification by chromatography (methylene chloride: methanol = 9: 1). ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.41 --8.41 (m, 1H), 8.42 --8.41 (m, 1H), 8.42 --8.41 (m, 1H), 8.39 (s, 1H), 8.10 --8.08 ( m, 1H), 8.09 (s, 1H), 7.83 (dd, J = 2.3, 8.7 Hz, 1H), 7.59 (d, J = 8.6 Hz, 1H), 6.04 (br s, 1H), 4.18 (dd, dd, J = 4.9, 13.2 Hz, 1H), 4.03 --3.94 (m, 1H), 3.62 --3.56 (m, 2H), 3.40 --3.25 (m, 2H), 3.01 --2.94 (m, 1H), 1.30 --1.25 ( m, 3H).

Step 2: Synthesis of compound WX080-3.

Add raw material WX080-2 (350 mg, 988.15 μmol), raw material BB-3 (743.66 mg, 1.68 mmol), solvent 1,4-dioxane (1 mL) and water (0.1 mL) to a pre-dried 15 mL reaction bottle. After that, potassium acetate (193.96 mg, 1.98 mmol) was added, replaced with nitrogen gas, and [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (72.30 mg, 98.81 μmol) was added. It was added, replaced with nitrogen gas, and further stirred at 90 ° C. for 12 hours. The reaction termination was detected by thin layer chromatography (methylene chloride: methanol = 10: 1). Water (10 mL) was added to the system, and the mixture was further extracted with methylene chloride (10 mL × 3). The obtained organic phase was dried over anhydrous sodium sulfate, and then rotationally dried under reduced pressure to perform preparative TLC (methylene chloride:). Purified by methanol = 15: 1) and further preparative HPLC (chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B%: 45% -45%, It was separated and purified by 15 min) to obtain the target compound WX080-3.

Step 3: Synthesis of compounds WX080 and WX081.

WX080-3 was separated by SFC (chromatography column: Agela Durashell C18 150 * 25mm 5 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; B%: 14% -44%, 10.5 min) , Enantiomer WX080 (holding time: 2.61 min) and WX081 (holding time: 1.668 min) were obtained. WX080: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.26 (d, J = 2.0 Hz, 1H), 8.15 (dd, J = 5.7, 8.8 Hz, 1H), 8.11-8.09 (m, 2H), 7.95 (d, J = 2.2 Hz, 1H), 7.82 --7.78 (m, 1H), 7.76 --7.72 (m, 1H), 7.48 (br s, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.17 --7.11 (m, 1H), 6.24 (br t, J = 5.4 Hz, 1H), 4.22 (dd, J = 4.9, 13.5 Hz, 1H), 4.03 (dd, J = 9.5, 13.2 Hz, 1H), 3.98 (s, 3H), 3.63 (t, J = 5.0 Hz, 2H), 3.45 --3.37 (m, 1H), 3.35 --3.27 (m, 1H), 3.05 --2.96 (m, 1H), 2.37 (br s, 1H), 1.31 (d, J = 7.1 Hz, 3H). WX081: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.24 (d, J = 1.8 Hz, 1H), 8.15 (dd, J = 5.7, 9.0 Hz, 1H), 8.12-8.07 (m, 2H), 7.93 (d, J = 2.2 Hz, 1H), 7.81 --7.77 (m, 1H), 7.75 --7.70 (m, 1H), 7.59 (br s, 1H), 7.25 (d, J = 2.4 Hz, 1H), 7.17 --7.11 (m, 1H), 6.35 (br s, 1H), 4.22 (dd, J = 4.7, 13.3 Hz, 1H), 4.03 (dd, J = 9.6, 13.3 Hz, 1H), 3.97 (s, 3H) , 3.63 (t, J = 5.0 Hz, 2H), 3.41 (dt, J = 5.1, 9.7 Hz, 1H), 3.35 --3.26 (m, 1H), 3.05 --2.97 (m, 1H), 2.53 (br s, 1H), 1.31 (d, J = 7.1 Hz, 3H).

Example 48: WX082, WX083

Step 1: Synthesis of compound WX082-2 WX082-1 (40.09 mg, 548.50 μmol, 47.00 μL) was added to a pre-dried 40 mL reaction bottle and then dissolved in methylene chloride (5 mL). This was followed by the addition of WX064-2 (150 mg, 274.25 μmol) and 1-propanephosphonic anhydride (cyclic trimmer) (261.78 mg, 411.38 μmol, 244.65 μL, 50% purity), and finally diisopropylethylamine (70.89 mg, 70.89 mg,). 548.50 μmol, 95.54 μL) was added dropwise. The reaction was stirred at 20 ° C. for 16 hours. The reaction termination was detected by TLC (methylene chloride: methanol = 20: 1). To the reaction system, 10 mL of water / 10 mL of ethyl acetate was added to dilute the mixture, and after separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, and purify by thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1). , WX082-2 was obtained.

Step 2: Synthesis of compounds WX082 and WX083
WX082-2 (130 mg) is supercritical fluid chromatography (chromatography column: Chiralpak AD-H 250 * 30 mm id 5 μ; mobile phase: A: CO2, B: IPA (0.1% NH ₃ H ₂ O); gradient: B % = 40%; Flow velocity: 60 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by enantiomer WX082 (holding time: 3.52 min) and WX083 (holding time: 3.87) min) was obtained. WX082: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (d, J = 1.8 Hz, 1H), 8.15 --8.08 (m, 2H), 8.04 (s, 1H), 7.96 (d, J = 2.2 Hz) , 1H), 7.85 --7.80 (m, 1H), 7.77 --7.72 (m, 1H), 7.53 (s, 1H), 7.26 --7.24 (m, 1H), 7.14 --7.07 (m, 1H), 6.19 (br d, J = 7.5 Hz, 1H), 5.03 --4.90 (m, 1H), 4.88 --4.83 (m, 1H), 4.79 (t, J = 7.1 Hz, 1H), 4.40 (t, J = 6.4 Hz, 1H) ), 4.21 --4.13 (m, 2H), 4.00 (dd, J = 9.3, 13.5 Hz, 1H), 3.96 (s, 3H), 3.08 --2.93 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H). MS, m / z = 602.2 [M + 1]. WX083: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.28 (d, J = 1.8 Hz, 1H), 8.15 --8.08 (m, 2H), 8.04 (s, 1H), 7.96 (d, J = 2.2 Hz) , 1H), 7.85 --7.80 (m, 1H), 7.77 --7.72 (m, 1H), 7.53 (s, 1H), 7.26 --7.24 (m, 1H), 7.14 --7.07 (m, 1H), 6.19 (br d, J = 7.5 Hz, 1H), 5.03 --4.90 (m, 1H), 4.88 --4.83 (m, 1H), 4.79 (t, J = 7.1 Hz, 1H), 4.40 (t, J = 6.4 Hz, 1H) ), 4.21 --4.13 (m, 2H), 4.00 (dd, J = 9.3, 13.5 Hz, 1H), 3.96 (s, 3H), 3.08 --2.93 (m, 1H), 1.29 (d, J = 6.8 Hz, 3H). MS, m / z = 602.2 [M + 1].

Example 49: WX084

Step 1: Synthesis of compound WX084-2 The raw material WX084-1 (500 mg, 1.85 mmol) was dissolved in tert-butanol (10 mL) in a pre-dried 40 mL flask, followed by diphenylazid phosphate (560.59 mg, 2.04). mmol, 441.41 μL) and triethylamine (224.86 mg, 2.22 mmol, 309.30 μL) were added and replaced with nitrogen gas. The reaction was stirred at 80 ° C. for 2 hours. After completion of the reaction, 10 mL saturated sodium bicarbonate / 10 mL ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by thin layer chromatography silica gel plate (petroleum ether: ethyl acetate = 10: 1). I got WX084-2. ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ = 8.85 (s, 1H), 8.31 (d, J = 1.8 Hz, 1H), 6.85 (br s, 1H), 1.54 --1.39 (m, 9H).

Step 2: Synthesis of compound WX084-3 WX084-2 (350 mg, 1.03 mmol) was added to a pre-dried 40 mL reaction bottle and then dissolved in hydrochloric acid / ethyl acetate (3 mL). The reaction was stirred at 20 ° C. for 16 hours. The reaction termination was detected by TLC (petroleum ether: ethyl acetate = 3: 1). 30 mL saturated sodium bicarbonate / 10 mL ethyl acetate was added to the reaction system for dilution, and after liquid separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give WX084-3. ^{1 1} H NMR (400 MHz, METHANOL-d4) δ = 7.89 (d, J = 1.8 Hz, 1H), 7.49 (d, J = 1.3 Hz, 1H).

Step 3: Synthesis of compound WX084-5 WX084-3 (120 mg, 497.91 μmol) is added to a pre-dried 40 mL flask and dissolved in tetrahydrofuran (6 mL), followed by sodium hydrogen hydrogen (99.58 mg, 2.49 mmol). Is added, the reaction solution is reacted at 0 ° C for 30 minutes, the solution is added to a solution of WX084-4 (148.26 mg, 647.28 μmol, 94.44 μL) in tetrahydrofuran (2 mL) at 20 ° C, and the reaction solution is added at 20 ° C. Was stirred for 1 hour. Then sodium hydrogen (99.58 mg, 2.49 mmol, 60% purity) was added and the reaction was stirred at 20 ° C. for 1 hour. Further, sodium hydrogen (99.58 mg, 2.49 mmol, 60% purity) was added, and the reaction solution was stirred at 20 ° C. for 1 hour. Further, sodium hydrogen (99.58 mg, 2.49 mmol, 60% purity) was added, and the reaction solution was stirred at 20 ° C. for 1 hour. After completion of the reaction, 10 mL saturated ammonium chloride / 10 mL ethyl acetate was added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1). , WX084-5 was obtained.

Step 4: Synthesis of compound WX084-6 WX084-5 (60 mg, 138.38 μmol) and bis (pinacolato) dichloromethane (38.65 mg, 152.21 μmol) were added to a pre-dried 40 mL reaction bottle to add 1,4-dioxane (1,4-dioxane). Dissolve in 3 mL), add potassium acetate (40.74 mg, 415.13 μmol), replace with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (10.13). mg, 13.84 μmol) was added. The reaction was stirred at 90 ° C. for 3 hours. After completion of the reaction, the reaction solution was directly filtered and spin-dried to obtain WX084-6, which was used as it was in the next step.

Step 5: Synthesis of compound WX084 WX084-6 (60 mg, 124.83 μmol), WX034-1 (60.70 mg, 187.24 μmol) and potassium carbonate (36.75 mg, 374.48 μmol) were added to a pre-dried 40 mL reaction bottle. It was dissolved in 1,4-dioxane (1 mL) and water (0.1 mL). Then, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (9.13 mg, 12.48 μmol) was added and replaced with nitrogen gas. The reaction was stirred at 90 ° C. for 16 hours. After completion of the reaction, 10 mL of water / 10 mL of ethyl acetate was added to the reaction system for dilution, and after separation, the organic phase was collected and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases are combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, concentrated under reduced pressure, and then purified by thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1). , Further preparative HPLC (Method: Chromatography Column: Agela Durashell C18 150 * 25mm 5μm; Mobile Phase: [Water (10mM NH ₄ HCO ₃ ) -ACN]; B%: 15% -45%, 10.5min) Then I got WX084. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.77 (s, 1H), 8.45 (d, J = 2.2 Hz, 1H), 8.13-8.05 (m, 2H), 7.81 (d, J = 8.6 Hz, 1H) ), 7.45 (dd, J = 2.5, 8.5 Hz, 1H), 7.25 (ddd, J = 2.6, 7.9, 8.9 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 4.02 (dd, dd, J = 9.7, 13.5 Hz, 1H), 3.04 --2.91 (m, 1H), 2.62 --2.55 (m, 3H), 1.22 (d, J = 7.1 Hz, 3H). MS, m / z = 598.1 [M + 1].

Example 50: WX085, WX086

Step 1: Synthesis of compound WX085-2 Compound WX085-1 (5 g, 22.93 mmol) and acetic acid (10 mL) are added sequentially to a pre-dried bite flask (100 mL), followed by anhydrous acetic acid (10.95 g, 107.22 mmol, 10.04 mL) and concentrated acetic acid (1.12 g, 11.38 mmol, 606.69 μL) were added. After that, it was replaced with nitrogen gas, heated to 60 ° C., and stirred for 2 hours. After completion of the reaction, the reaction solution was slowly added dropwise to ice water (40 mL), stirred for 10 minutes, filtered, the cake was washed with water (20 mL × 2), and the cake was freeze-dried to remove the remaining water. It was removed to obtain the target compound WX085-2. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 9.82 (br s, 1H), 8.70 (d, J = 2.3 Hz, 1H), 8.63 (d, J = 2.3 Hz, 1H), 2.46 (s, 3H) ..

Step 2: Synthesis of compound WX085-3.

Compound WX085-2 (3.6 g, 13.84 mmol), ammonium chloride (8.89 g, 166.13 mmol, 5.81 mL), methanol (180 mL) and water (90 mL) were added in this order to a pre-dried three-necked flask, and finally. Zinc powder (6.34 g, 96.91 mmol) was added slowly, then replaced with nitrogen gas and stirred at 20 ° C. for 2 hours. The reaction was terminated by TLC (petroleum ether / ethyl acetate = 1/1). After filtering, further washing with methanol (100 mL × 3), combining the filtrates, rotating and drying under reduced pressure, and further extracting with saturated sodium bicarbonate (100 mL) and ethyl acetate (300 mL × 4), organic. The phases are combined, washed with saturated sodium chloride (200 mL), dried over anhydrous sodium sulfate, and finally concentrated under reduced pressure by column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1: 1). Purification gave compound WX085-3. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 7.74 (d, J = 2.1 Hz, 1H), 7.37 (d, J = 2.1 Hz, 1H), 2.16 (s, 3H).

Step 3: Synthesis of compound WX085-5.

Compound WX085-3 (1.1 g, 4.78 mmol) and pyridine (10 mL) were added in this order to a pre-dried reaction bottle, and finally compound WX085-4 (1.20 g, 5.26 mmol, 767.33 μL) was added. It was then replaced with nitrogen gas and stirred at 50 ° C. for 10 hours. The reaction was terminated by TLC (ethyl acetate). The solvent was spin-dried under reduced pressure and then purified by column chromatography (petroleum ether: ethyl acetate = 5: 1-0: 1) to give compound WX085-5. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 9.40 (br s, 1H), 8.18 (d, J = 2.0 Hz, 1H), 8.02 --7.95 (m, 2H), 7.71 (br s, 1H), 7.26 (d, J = 2.6 Hz, 1H), 7.06 (ddd, J = 2.6, 7.4, 8.9 Hz, 1H), 2.28 (s, 3H).

Step 4: Synthesis of compound WX085-6.

Compound WX085-5 (0.5 g, 1.18 mmol), bis (pinacolato) diboron (330.45 mg, 1.30 mmol), potassium acetate (232.20 mg, 2.37 mmol) and 1,4- in a pre-dried reaction bottle (10 mL). Dioxane (5 mL) was added in sequence, replaced with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (86.56 mg, 118.30 μmol) was added. After that, it was replaced with nitrogen gas, heated to 110 ° C., and stirred for 10 hours. After completion of the reaction, the temperature of the reaction solution was lowered, and then the solvent was distilled under reduced pressure to obtain compound WX085-6, which was used as it was in the next step.

Step 5: Synthesis of compound WX085-7.

Compound WX034-1 (414.08 mg, 1.28 mmol), compound WX085-6 (0.6 g, 1.28 mmol), potassium acetate (376.08 mg, 3.83 mmol) and solvent 1,4-dioxane (5 mL) in a pre-dried reaction bottle. ) And water (0.5 mL) were added in that order. After replacement with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (93.47 mg, 127.74 μmol) was added, further replaced with nitrogen gas, and heated to 110 ° C. Stirred for 10 hours. The reaction was terminated by TLC (methylene chloride / methanol = 10/1). After lowering the temperature of the reaction solution, the solvent was distilled under reduced pressure and purified by column chromatography (petroleum ether: ethyl acetate = 5: 1 to 1: 1) to obtain compound WX085-7. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.55 (s, 1H), 8.43 (d, J = 2.0 Hz, 1H), 8.27 --8.15 (m, 3H), 8.09 (dd, J = 2.1, 8.5 Hz) , 1H), 7.92 (dd, J = 5.8, 8.8 Hz, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.62 --7.74 (m, 6H), 7.18 (dt, J = 2.4, 8.4 Hz, 1H), 4.34 --4.17 (m, 2H), 4.09 --3.95 (m, 2H), 3.60 (s, 1H), 3.05 --2.92 (m, 2H), 2.63 --2.61 (m, 3H), 2.22 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Step 6: Synthesis of compound WX085-8.

Compound WX085-7 (0.28 g, 476.98 μmol), methanol (10 mL), and potassium carbonate (197.77 mg, 1.43 mmol) were added in this order to a pre-dried reaction bottle. After that, it was replaced with nitrogen gas, heated to 80 ° C., and stirred for 10 hours. After completion of the reaction, the reaction solution was cooled and then concentrated under reduced pressure, and preparative HPLC (purification method: chromatography column: Agela Durashell C18 150 * 25 mm 5 μm; mobile phase: [water (10 mM NH4HCO3) -ACN]; B %: 12% -42%, 10.5 min) to give compound WX085-8. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.17 (d, J = 2.0 Hz, 1H), 8.15 (s, 1H), 8.11 (dd, J = 3.3, 9.3 Hz, 1H), 8.01 --7.91 (m) , 1H), 7.87 (dd, J = 2.1, 8.5 Hz, 1H), 7.72 --7.66 (m, 1H), 7.54 --7.44 (m, 2H), 7.28 --7.20 (m, 1H), 4.23 (dd, J) = 5.0, 13.4 Hz, 1H), 4.01 (dd, J = 9.9, 13.4 Hz, 1H), 2.99 (br dd, J = 9.7, 11.9 Hz, 1H), 2.61 (s, 3H), 1.23 (d, J) = 6.9 Hz, 3H).

Step 7: Synthesis of compounds WX085 and WX086.

Compound WX085-8 (0.1 g, 183.49 μmol) is supercritical chromatographic preparative SFC (separation method: chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OMeOH]; B Purification by%: 40% -40%, 13 min) gave enantiomer WX085 (retention time 3.28 min) and compound WX086 (retention time 3.90 min). WX085: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.18 --8.13 (m, 2H), 8.10 (dd, J = 5.9, 8.9 Hz, 1H), 8.01 (br s, 1H), 7.85 (dd, J) = 2.1, 8.5 Hz, 1H), 7.69 (d, J = 8.5 Hz, 1H), 7.54 --7.74 (m, 2H), 7.29 --7.21 (m, 1H), 4.23 (dd, J = 4.9, 13.3 Hz, 1H), 4.01 (dd, J = 9.8, 13.4 Hz, 1H), 3.05 --2.92 (m, 1H), 2.65 --2.58 (m, 3H), 1.23 (d, J = 7.0 Hz, 3H). Compound WX086: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.19 --8.14 (m, 2H), 8.13 --8.06 (m, 1H), 8.01 (br s, 1H), 7.86 (dd, J = 2.2, 8.6) Hz, 1H), 7.72 --7.76 (m, 1H), 7.53 --7.44 (m, 2H), 7.28 --7.20 (m, 1H), 4.23 (dd, J = 5.0, 13.3 Hz, 1H), 4.02 (dd, dd, J = 9.7, 13.5 Hz, 1H), 3.04 --2.93 (m, 1H), 2.62 (s, 3H), 1.23 (d, J = 6.8 Hz, 3H).

Example 51: WX087, WX088

Step 1: Synthesis of compound WX087-2 Compound BB-2 (2 g, 5.90 mmol) was dissolved in dioxane (20 mL) and water (4 mL), to which compound WX087-1 (1.77 g, 7.08 mmol), Pd. (dppf) Cl ₂ (963.06 mg, 1.18 mmol) and potassium acetate (2.31 g, 23.59 mmol) were added, and the reaction solution was stirred under the condition of 100 ° C. under nitrogen gas protection for 3 hours after the reaction was completed. The reaction mixture was rotationally dried. The obtained residue was separated by a chromatography column (eluent: methanol / methylene chloride = 5 to 10%) to obtain the target compound WX087-2. MS-ESI m / z: 383.1 [M + H] ⁺ .

Step 2: Synthesis of compound WX087-3 Compound WX087-2 (2.3 g, 6.01 mmol) was dissolved in methylamine ethanol solution (2 M, 50 mL), and the reaction solution was stirred under the condition of 80 ° C. for 10 hours. .. After completion of the reaction, the reaction solution was spin-dried. The target compound WX087-3 was obtained. MS-ESI m / z: 368.1 [M + H] ⁺ .

Step 3: Synthesis of compound WX087-5 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), compound WX087-4 (144.46 mg, 742.32 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried and separated by preparative HPLC separation (TFA) to obtain the target compound WX087-5. MS-ESI m / z: 526.1 [M + H] ⁺ .

Step 4: Synthesis of Compounds WX087 and WX088 Compound WX087-5 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm), elution condition: 0.1% NH ₃ H ₂ OEtOH, EtOH; B. %: 55% -55%, flow velocity (ml / min): 80 mL / min) to obtain enantiomers WX087 (retention time 0.863 min) and WX088 (retention time 2.485 min). WX087: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.32 (d, J = 1.8 Hz, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.06 (dd, J = 8.5, 2.3 Hz, 1 H), 7.89 (d, J = 2.5 Hz, 2 H), 7.79 --7.84 (m, 2 H), 7.76 (d, J = 8.5 Hz, 1 H) , 7.40 (t, J = 8.9 Hz, 2 H), 4.03 --4.11 (m, 1 H), 3.97 (dd, J = 13.3, 9.0 Hz, 1 H), 3.69 (s, 3 H), 2.87 (br dd, J = 14.8, 7.0 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 526.1 [M + H] ⁺ . WX088: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.31 --8.36 (m, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.07 (dd) , J = 8.5, 2.0 Hz, 1 H), 7.87 --7.93 (m, 2 H), 7.82 (dd, J = 8.8, 5.3 Hz, 1 H), 7.79 --7.84 (m, 1 H), 7.41 (t) , J = 8.8 Hz, 2 H), 4.02 --4.13 (m, 1 H), 3.97 (dd, J = 13.2, 9.2 Hz, 1 H), 3.69 (s, 3 H), 2.81 --2.94 (m, 1) H), 2.48 --2.49 (m, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 526.1 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 52: WX089, WX090

Step 1: Synthesis of compound WX089-2 Compound WX087-3 (0.3 g, 816.55 μmol) was dissolved in pyridine (5 mL), and compound WX089-1 (157.82 mg, 742.32 μmol, 99.88 μL) was added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC (TFA) separation to obtain the target compound WX089-2. MS-ESI m / z: 544.1 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX089 and WX090 Compound WX089-2 is supercritical fluid chromatography (separation conditions: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; Separation by B%: 55% -55%) gave enantiomers WX089 (holding time 0.711 min) and WX090 (holding time 2.308 min). WX089: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.22 --8.36 (m, 2 H), 8.18 (s, 1 H), 8.06 (dd, J = 8.4, 2.1 Hz, 1 H), 7.82 --7.93 (m, 2 H), 7.72 --7.81 (m, 2 H), 7.50 (br t, J = 9.2 Hz, 1 H), 7.16 --7.22 (m, 1 H), 4.03 --4.17 (m, 1) H), 3.87 --4.02 (m, 1 H), 3.70 (s, 3 H), 2.87 (dq, J = 14.5, 7.1 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 544.1 [M + H] ⁺ . WX090: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.22 --8.36 (m, 2 H), 8.18 (s, 1 H), 8.06 (dd, J = 8.4, 2.1 Hz, 1 H), 7.82 --7.93 (m, 2 H), 7.72 --7.81 (m, 2 H), 7.50 (br t, J = 9.2 Hz, 1 H), 7.16 --7.22 (m, 1 H), 4.03 --4.17 (m, 1) H), 3.87 --4.02 (m, 1 H), 3.70 (s, 3 H), 2.87 (dq, J = 14.5, 7.1 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 544.1 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 53: WX091, WX092

Step 1: Synthesis of compound WX091-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), compound WX091-1 (151.93 mg, 742.32 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX091-2. MS-ESI m / z: 536.1 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX091 and WX092 Compound WX091-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B Separation by%: 55% -55%, flow velocity (ml / min): 80 mL / min) gave enantiomers WX091 (holding time 0.796 min) and WX092 (holding time 2.452 min). WX091: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.20 --8.30 (m, 1 H), 8.18 (br d, J = 2.5 Hz, 2 H), 7.94 --8.04 (m, 1 H), 7.90 (br d, J = 4.5 Hz, 1 H), 7.77 --7.82 (m, 1 H), 7.71 --7.77 (m, 1 H), 7.64 (d, J = 7.8 Hz, 1 H), 7.19 (s) , 1 H), 7.10 (br d, J = 8.3 Hz, 1 H), 4.04 --4.13 (m, 1 H), 3.90 --4.01 (m, 1 H), 3.73 (s, 3 H), 2.76 --3.02 (m, 1 H), 2.60 (s, 3 H), 2.29 (s, 3 H), 1.08 (br d, J = 6.8 Hz, 3 H). MS-ESI m / z: 536.1 [M + H] ⁺ . WX092: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.31 (d, J = 2.0 Hz, 1 H), 8.20 (d, J = 5.2 Hz, 2 H), 8.03 (dd, J = 8.5, 2.0 Hz, 1 H), 7.87 --7.93 (m, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.63 (d, J = 8.0) Hz, 1 H), 7.23 (s, 1 H), 7.12 (br d, J = 8.0 Hz, 1 H), 4.03 --4.13 (m, 1 H), 3.97 (br dd, J = 13.2, 9.2 Hz, 1 H), 3.74 (s, 3 H), 2.87 (br dd, J = 14.6, 7.0 Hz, 1 H), 2.62 (s, 3 H), 2.30 (s, 3 H), 1.09 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 536.1 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 54: WX093, WX094

Step 1: Synthesis of compound WX093-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), compound WX093-1 (159.74 mg, 816.55 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX093-2. MS-ESI m / z: 527.1 [M + H] ⁺ , 549.1 [M + Na] ⁺ .

Step 2: Synthesis of Compounds WX093 and WX094 Compound WX093-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; Separation was performed by B%: 55% -55%, flow velocity (ml / min): 80 mL / min) to obtain enantiomers WX093 (holding time 0.473 min) and WX094 (holding time 1.176 min). WX093: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.33 (br s, 1 H), 8.26 (s, 1 H), 8.18 (s, 1 H), 8.09 (br d, J = 8.5 Hz) , 1 H), 7.89 (br d, J = 4.3 Hz, 2 H), 7.73 --7.79 (m, 1 H), 4.05- 4.10 (m, 1 H), 3.93 --4.00 (m, 1 H), 3.74 (s, 3 H), 2.86 (br dd, J = 15.1, 6.3 Hz, 1 H), 2.48 (br s, 3 H), 2.37 (s, 3 H), 2.26 (s, 3 H), 1.08 ( d, J = 6.8 Hz, 3 H). MS-ESI m / z: 527.1 [M + H] ⁺ , 549.1 [M + Na] ⁺ . WX094: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.36 (br s, 1 H), 8.26 (s, 1 H), 8.18 (s, 1 H), 8.10 (br d, J = 8.5 Hz) , 1 H), 7.89 (br d, J = 4.5 Hz, 2 H), 7.76 (d, J = 8.5 Hz, 1 H), 4.04 --4.12 (m, 1 H), 3.96 (dd, J = 13.1, 9.0 Hz, 1 H), 3.74 (s, 3 H), 2.81 --2.92 (m, 1 H), 2.35 (s, 2 H), 2.26 (s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 527.1 [M + H] ⁺ , 549.1 [M + Na] ⁺ . The proportion of the two isomers was 1: 1.

Example 55: WX095, WX096

Step 1: Synthesis of compound WX095-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), compound WX095-1 (201.73 mg, 816.55 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX095-2. MS-ESI m / z: 578.0 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX095 and WX096 Compound WX095-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O IPA]. Separation was performed by B%: 40% -40%, flow velocity (ml / min): 80 mL / min) to obtain enantiomers WX095 (holding time 3.939 min) and WX096 (holding time 3.580 min). WX095: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.20 --8.33 (m, 2 H), 8.17 (s, 1 H), 8.06 (dd, J = 8.4, 2.1 Hz, 1 H), 7.86 --7.94 (m, 3 H), 7.75 (d, J = 8.5 Hz, 2 H), 4.02 --4.11 (m, 1 H), 3.96 (dd, J = 13.2, 9.2 Hz, 1 H), 3.73 (s) , 3 H), 2.86 (br dd, J = 14.7, 6.9 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 578.0 [M + H] ⁺ . WX096: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.42 (d, J = 2.0 Hz, 1 H), 8.29 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.10 (dd, J = 8.5, 2.3 Hz, 1 H), 7.98 (d, J = 2.3 Hz, 1 H), 7.90 --7.94 (m, 1 H), 7.89 (s, 1 H), 7.83 --7.87 ( m, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 4.02 --4.14 (m, 1 H), 3.97 (dd, J = 13.3, 9.0 Hz, 1 H), 3.70 (s, 3 H) ), 2.82 --2.93 (m, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 578.0 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 56: WX097, WX098

Step 1: Synthesis of compound WX097-2 Compound WX087-3 (0.3 g, 816.55 μmol) was dissolved in pyridine (5 mL), and compound WX097-1 (199.74 mg, 816.55 μmol, 130.55 μL) was added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX097-2. MS-ESI m / z: 576.0 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX097 and WX098 Compound WX097-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O EtOH]; B Separation by%: 55% -55%, flow velocity (ml / min): 80 mL / min) gave enantiomers WX097 (retention time 0.567 min) and WX098 (retention time 1.348 min). WX097: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.38 (s, 1 H), 8.28 (d, J = 2.3 Hz, 1 H), 8.19 (s, 1 H), 8.01 --8.12 (m) , 3 H), 7.94 --8.01 (m, 2 H), 7.89 (br d, J = 4.8 Hz, 1 H), 7.80 (t, J = 7.5 Hz, 1 H), 7.76 (d, J = 8.5 Hz) , 1 H), 4.02 --4.12 (m, 1 H), 3.97 (dd, J = 13.2, 9.2 Hz, 1 H), 3.59 (s, 3 H), 2.87 (br dd, J = 15.1, 7.0 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 576.0 [M + H] ⁺ . WX098: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.41 (d, J = 2.3 Hz, 1 H), 8.28 (d, J = 2.0 Hz, 1 H), 8.20 (s, 1 H), 8.08 (s, 3 H), 7.99 (br d, J = 8.0 Hz, 1 H), 7.95 --7.97 (m, 1 H), 7.87 --7.95 (m, 1 H), 7.78 --7.84 (m, 1 H) ), 7.76 (d, J = 8.1 Hz, 1 H), 4.08 (dd, J = 13.2, 5.6 Hz, 1 H), 3.93 --4.02 (m, 1 H), 3.59 (s, 3 H), 2.82- 2.91 (m, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 576.0 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 57: WX099, WX100

Step 1: Synthesis of compound WX099-2 Compound WX087-3 (0.3 g, 816.55 μmol) was dissolved in pyridine (5 mL), and compound WX099-1 (199.74 mg, 816.55 μmol, 125.62 μL) was added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX099-2. MS-ESI m / z: 576.0 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX099 and WX100 Compound WX099-2 is supercritical fluid chromatography (separation conditions: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B Separation by%: 55% -55%, flow velocity (ml / min): 80 mL / min) gave enantiomers WX099 (holding time 0.583 min) and WX100 (holding time 1.365 min). WX099: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.36 (br s, 1 H), 8.23 (s, 1 H), 8.18 (s, 1 H), 8.01 --8.08 (m, 2 H) , 7.99 (br d, J = 3.8 Hz, 1 H), 7.86 --7.92 (m, 2 H), 7.81 --7.86 (m, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 4.02- 4.11 (m, 1 H), 3.96 (dd, J = 13.3, 9.3 Hz, 1 H), 3.64 (s, 3 H), 2.81 --2.91 (m, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 576.0 [M + H] ⁺ . WX100: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.39 (d, J = 2.3 Hz, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 7.99 --8.09 (m, 3 H), 7.91 (br d, J = 2.3 Hz, 2 H), 7.82 --7.87 (m, 2 H), 7.76 (d, J = 8.5 Hz, 1 H), 4.01 --4.10 (m, 1 H), 3.96 (dd, J = 13.2, 8.9 Hz, 1 H), 3.63 (s, 3 H), 2.86 (br dd, J = 14.9, 6.4 Hz, 1 H), 2.48 (br s) , 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 576.0 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 58: WX101, WX102

Step 1: Synthesis of compound WX101-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), and compound WX101-1 (173.60 mg, 816.55 μmol, 110.57 μL) is added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX101-2. MS-ESI m / z: 544.0 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX101 and WX102 Compound WX101-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; Separation was performed by B%: 55% -55%, flow velocity (ml / min): 80 mL / min) to obtain enantiomers WX101 (holding time 0.841 min) and WX102 (holding time 2.518 min). WX101: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.21 --8.36 (m, 2 H), 8.18 (s, 1 H), 8.06 (br d, J = 7.0 Hz, 1 H), 7.90 ( br d, J = 4.3 Hz, 2 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.62 --7.70 (m, 1 H), 7.24 (br t, J = 9.0 Hz, 2 H), 4.01 --4.15 (m, 1 H), 3.96 (dd, J = 13.3, 9.3 Hz, 1 H), 3.67 (s, 3 H), 2.81 --2.91 (m, 1 H), 2.48 (br s, 3 H) , 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 544.0 [M + H] ⁺ . WX102: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 (d, J = 2.0 Hz, 2 H), 8.18 (s, 1 H), 8.07 (br d, J = 8.3 Hz, 1 H) , 7.86 --7.95 (m, 2 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.64 --7.73 (m, 1 H), 7.25 (br t, J = 9.2 Hz, 2 H), 4.02- 4.11 (m, 1 H), 3.96 (dd, J = 13.2, 9.2 Hz, 1 H), 3.66 (s, 3 H), 2.87 (br dd, J = 15.1, 7.0 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 544.0 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 59: WX103, WX104

Step 1: Synthesis of compound WX103-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), compound WX103-1 (255.27 mg, 816.55 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC separation (TFA) to obtain the target compound WX103-2. MS-ESI m / z: 644.1 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX103 and WX104 Compound WX103-2 is supercritical fluid chromatography (separation condition: chromatography column: C2 250 mm * 30 mm, 10 μm; mobile phase: [0.1% NH ₃ H ₂ OMeOH]; B%: Separation was performed by 40% -40%, flow rate (ml / min): 80 mL / min) to obtain enantiomers WX103 (retention time 5.201 min) and WX104 (retention time 6.417 min). WX103: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.39 (br s, 1 H), 8.29 (s, 2 H), 8.22 --8.28 (m, 2 H), 8.18 (s, 1 H) , 8.04 (dd, J = 8.5, 2.0 Hz, 1 H), 7.87 --7.94 (m, 2 H), 7.74 (d, J = 8.5 Hz, 1 H), 4.02 --4.12 (m, 1 H), 3.96 (dd, J = 13.2, 9.2 Hz, 1 H), 3.62 (s, 3 H), 2.82 --2.91 (m, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 644.1 [M + H] ⁺ . WX104: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.47 (s, 1 H), 8.36 (br s, 1 H), 8.30 (s, 3 H), 8.19 (s, 1 H), 8.08 (br d, J = 8.5 Hz, 1 H), 7.98 (s, 1 H), 7.89 (br d, J = 4.5 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 4.03- 4.17 (m, 1 H), 3.97 (dd, J = 13.2, 9.2 Hz, 1 H), 3.58 (s, 3 H), 2.82 --2.91 (m, 1 H), 2.52 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 644.1 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 60: WX105, WX106

Step 1: Synthesis of compound WX105-2.

Compound WX105-1 (4 g, 25.79 mmol) and NBS (4.59 g, 25.79 mmol) were added to DCM (50 mL) and stirred at 25 ° C. for 2 hours. After completion of the reaction, the reaction solution was filtered, the cake was washed with DCM (50 mL), and the cake was dried to obtain compound WX105-2. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 7.63 --7.66 (m, 2 H), 7.54 (d, J = 2.5 Hz, 1 H), 7.51 (d, J = 2.0 Hz, 1 H).

Step 2: Synthesis of compound WX105-3.

Compound WX105-2 (1.00 g, 4.27 mmol), Compound BB2-4 (0.84 g, 6.40 mmol), EDCI (0.83 g, 4.33 mmol), TEA (1.73 g, 17.09 mmol), HOPO (0.55 g, 4.95 mmol) Was added to DCM (50 mL) and stirred at 50 ° C. for 16 hours. After completion of the reaction, the reaction solution was rotat-dried, the residue was diluted with water (100 mL), extracted with DCM (100 mL), the organic phase was rotat-dried, and the obtained product was obtained by chromatography column (ethyl acetate: petroleum). Separation with ether = 0% to 10%) gave compound WX105-3. ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.59 (t, J = 5.5 Hz, 1 H), 7.54 (d, J = 1.5 Hz, 1 H), 7.44 (dd, J = 10.8, 2.3 Hz , 1 H), 6.44 (s, 2 H), 4.03 --4.08 (m, 1 H), 4.06 (br s, 1 H), 3.38 --3.47 (m, 1 H), 3.22 --3.31 (m, 1 H) ), 2.69 --2.77 (m, 1 H), 1.15 --1.19 (m, 3 H), 1.09 (d, J = 7.0 Hz, 3 H).

Step 3: Synthesis of compound WX105-4.

Compound WX105-3 (0.6 g, 1.73 mmol) was added to formic acid (12.20 g, 265.07 mmol, 10 mL) and stirred at 100 ° C. for 16 hours. After completion of the reaction, the reaction mixture was spin-dried, diluted with water (50 mL), extracted with DCM (50 mL), and the organic phase was spin-dried to give compound WX105-4. MS-ESI m / z: 359.0 [M + H] ⁺ .

Step 4: Synthesis of compound WX105-5.

Compound WX105-4 (0.6 g, 1.34 mmol), BB-3 (0.63 g, 1.34 mmol), Pd (dppf) Cl _{2 (} 0.098 g, 133.93 μmol), KOAc (0.527 g, 5.37 mmol) in dioxane (8 mL) ) And water (1.6 mL), the system was replaced 3 times with nitrogen gas, followed by stirring at 100 ° C. for 1 hour under nitrogen gas protection. After completion of the reaction, the reaction mixture was spin-dried, diluted with water (50 mL), and further extracted with DCM (50 mL). The organic phase was spin-dried, and the obtained product was separated by a chromatography column (methanol: methylene chloride = 0% to 3%) to obtain compound WX105-5. MS-ESI m / z: 593.0 [M + H] ⁺ .

Step 5: Synthesis of Compound WX105-6 Compound WX105-5 (0.4 g, 635.75 μmol) was added to a methylamine solution (78.98 mg, 635.75 μmol, 10 mL) and stirred at 80 ° C. for 16 hours. After completion of the reaction, the reaction mixture was spin-dried and preparative HPLC (Phenomenex Gemini C18 250 * 50mm * 10 μm; mobile phase: [water (0.05% ammonium hydroxide v / v) -ACN]; B%: 30%- Purification by 40%, 8 min) gave compound WX105-6.

Step 6: Synthesis of compounds WX105 and WX106.

WX105-6 was separated by SFC (col μmn: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 55% -55%) and compound WX105 (Rt = 5.372 min). ) And compound WX106 (Rt = 6.218min). WX105: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.13 (d, J = 2.0 Hz, 1 H), 8.10 (s, 1 H), 7.97 --8.05 (m, 2 H), 7.88 (d) , J = 2.5 Hz, 1 H), 7.73 (br d, J = 11.5 Hz, 1 H), 7.37 (dd, J = 8.5, 2.5 Hz, 1 H), 7.14 (td, J = 8.3, 2.5 Hz, 1 H), 4.14 (dd, J = 13.6, 5.0 Hz, 1 H), 3.95 (dd, J = 13.3, 9.8 Hz, 1 H), 3.77 (s, 3 H), 2.85 --2.95 (m, 1 H) ), 2.53 (s, 3 H), 1.14 (d, J = 7.0 Hz, 3 H). Compound WX106: ¹ H NMR (400 MHz, METHANOL-d ₄ ) δ ppm 8.07 --8.13 (m, 2 H), 7.95 --8.03 (m, 2 H), 7.86 (d, J = 2.0 Hz, 1 H), 7.70 (dd, J = 11.3, 1.8 Hz, 1 H), 7.37 (dd, J = 8.5, 2.5 Hz, 1 H), 7.14 (td, J = 8.3, 2.5 Hz, 1 H), 4.14 (dd, J = 13.6, 5.0 Hz, 1 H), 3.90 --4.02 (m, 1 H), 3.76 (s, 3 H), 2.82 --2.97 (m, 1 H), 2.53 (s, 3 H), 1.14 (d, J = 7.0 Hz, 3 H).

Example 61: WX107, WX108

Step 1: Synthesis of compound WX107-2 Compound WX107-1 (4 g, 31.46 mmol) and potassium carbonate (8.70 g, 62.92 mmol) were dissolved in DMF (5 mL) and ethyl iodide (4.91 g, 4.91 g,) was dissolved at 0 ° C. 31.46 mmol) was added and stirred at 25 ° C. overnight. After completion of the reaction, the mixture was poured into water (100 mL) and extracted with methylene chloride (100 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtration to remove the desiccant, the solvent was removed under reduced pressure and purified by column chromatography (ethyl acetate / petroleum ether = 0-10%) to give compound WX107-2. ¹ H NMR (400MHz, Methanol-d ₄ ) δ: 4.36 --4.17 (m, 2H), 4.12 (q, J = 7.1 Hz, 1H), 2.03 --1.86 (m, 2H), 1.39 --1.27 (m, 3H) ), 1.15 --1.04 (m, 3H).

Step 2: Synthesis of compound WX107-3 Compound WX107-2 (2.0 g, 14.17 mmol) and concentrated hydrochloric acid (1.08 mL) are dissolved in methanol (25 mL), and Rainy Ni (242.75 mg, 2.83 mmol) is protected by nitrogen gas. ) Was added, hydrogen gas (50 psi) was introduced, and the mixture was stirred at 30 ° C. overnight. After completion of the reaction, the solvent was removed under reduced pressure to obtain compound WX107-3. ^{1 1} H NMR (400MHz, Methanol-d ₄ ) δ: 4.29 --4.05 (m, 2H), 2.91 --2.66 (m, 2H), 2.49 --2.06 (m, 1H), 1.69 --1.51 (m, 2H), 1.33 --1.22 (m, 3H), 1.05 --0.90 (m, 3H).

Step 3: Synthesis of Compound WX107-4 Compound 2-amino-5-bromobenzoic acid (0.5 g, 2.31 mmol) was dissolved in DMF (10 mL) and DIEA (298.54 mg, 2.31 mmol) and HATU (878.33 mg, 2.31 mmol) and WX107-3 (419.63 mg, 2.31 mmol) were added and stirred at 25 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (10 mL) and extracted with ethyl acetate (10 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure, and purification was performed by column chromatography (eluent: ethyl acetate / petroleum ether = 0-20%) to obtain the target compound WX107-4. ¹ H NMR (400MHz, Methanol-d ₄ ) δ: 7.65 --7.38 (m, 1H), 7.27 (dd, J = 2.3, 8.8 Hz, 1H), 6.69 (d, J = 8.8 Hz, 1H), 4.18 ( q, J = 7.3 Hz, 2H), 3.54 --3.40 (m, 2H), 2.83 --2.54 (m, 1H), 1.80 --1.45 (m, 2H), 1.36 --1.21 (m, 3H), 1.05 --0.91 ( m, 3H). MS-ESI m / z: 344.9 [M + H] ⁺ , 346.9 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX107-5 Compound WX107-4 (0.4 g, 1.17 mmol) is dissolved in ethanol (80 mL), formamidine acetate (364.00 mg, 3.50 mmol) is added, and the temperature is 80 ° C. for 2 hours. Stirred. After completion of the reaction, the organic solvent was spin-dried, poured into water (20 mL), and extracted with methylene chloride (20 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX107-5, which was used as it was in the next step. MS-ESI m / z: 352.9 [M + H] ⁺ , 354.9 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX107-6 Compound WX107-5 (0.25 g, 707.79 μmol), BB-2 (313.34 mg, 707.79 μmol), potassium acetate (277.85 mg, 2.83 mmol) was added to dioxane (2 mL) and water (2 mL). It was dissolved in 0.2 mL), after which Pd (dppf) Cl ₂ (10.36 mg, 14.16 μmol) was added, heated to 95 ° C. under the protection of nitrogen gas, and stirred for 2 hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (20 mL), and extracted with methylene chloride (20 mL × 3). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure and separated by a preparative chromatography plate (methanol / methylene chloride = 1:30) to obtain the target compound WX107-6. MS-ESI m / z: 589.1 [M + H] ⁺ , 591.1 [M + H + 2] ⁺ .

Step 6: Synthesis of compound WX107-7
WX107-6 (0.1 g, 178.26 μmol) was dissolved in a methylamine alcohol solution (20 mL), heated to 80 ° C. and stirred overnight. After completion of the reaction, the mixture was cooled to room temperature, the solvent was removed under reduced pressure, and the mixture was separated by a preparative chromatography plate (methanol / methylene chloride / triethylamine = 1: 20: 0.2) to obtain the target compound WX107-7. MS-ESI m / z: 561.0 [M + H] ⁺ , 563.0 [M + H + 2] ⁺ .

Step 7: Synthesis of compound WX107-8 Compound WX107-7 (0.1 g, 178.26 μmol) is dissolved in DMF (2 mL), TEA (36.08 mg, 356.52 μmol, and HATU (67.78 mg, 178.26 μmol), methylamine. Hydrochloride (12.04 mg, 178.26 μmol) was added and stirred at 30 ° C. for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, poured into water (10 mL) and in methylene chloride (10 mL × 3). Extracted. The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent was removed under reduced pressure and a preparative chromatography plate (eluent: eluent: Separation by methanol / methylene chloride = 1: 20), and further HPLC preparative column (AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 55% -55% , min) to obtain the target compound WX107-8.

Step 8: Synthesis of Compounds WX107 and WX108 Compound WX107-8 is supercritical fluid chromatography (chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 55. The enantiomers WX107 and WX108 were obtained by separation by% -55%). The retention times were 0.729 min and 1.837 min, respectively, and the proportion was 1: 1. WX107: ^{1 1} H NMR (400MHz, CDCl ₃ ) δ: 8.21 (d, J = 2.0 Hz, 1H), 8.11-8.02 (m, 2H), 8.01 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.82 --7.73 (m, 1H), 7.73 --7.60 (m, 1H), 7.22 --7.19 (m, 1H), 7.11 --6.97 (m, 1H), 5.55 (br d, J = 4.5 Hz, 1H) ), 4.21 (dd, J = 4.5, 13.3 Hz, 1H), 4.00 --3.87 (m, 4H), 2.67 (m, 4H), 1.76 --1.63 (m, 1H), 1.63 --1.47 (m, 3H), 0.94 (t, J = 7.4 Hz, 3H). MS-ESI m / z: 574.1 [M + H] ⁺ , 576.1 [M + H + 2] ⁺ . WX108: ^{1 1} H NMR (400MHz, CDCl ₃ ) δ: 8.20 (d, J = 1.8 Hz, 1H), 8.10 --8.01 (m, 2H), 8.01 (s, 1H), 7.90 (d, J = 2.3 Hz, 1H), 7.79 --7.70 (m, 1H), 7.70 --7.65 (m, 1H), 7.22 --7.20 (m, 1H), 7.10 --7.00 (m, 1H), 5.58 (br d, J = 4.5 Hz, 1H) ), 4.21 (dd, J = 4.5, 13.1 Hz, 1H), 3.96 --3.85 (m, 4H), 2.67 (d, J = 5.0 Hz, 3H), 2.84 --2.55 (m, 1H), 1.76 --1.63 ( m, 1H), 1.75 --1.48 (m, 1H), 1.63 --1.47 (m, 2H), 0.94 (t, J = 7.4 Hz, 3H). MS-ESI m / z: 574.1 [M + H] ⁺ , 576.1 [M + H + 2] ⁺ .

Example 62: WX109, WX110, WX111, WX112

Step 1: Synthesis of compound WX109-2 WX024-1 (380 mg, 1.22 mmol, 1 eq) and WX109-1 (174.03 mg, 1.34 mmol, 1.1 eq, HCl) are added to a pre-dried 40 mL reaction bottle. After that, it was dissolved in the solvent methylene chloride (10 mL). The reaction was cooled to 0 ° C., followed by 1-propanephosphonic anhydride (cyclic trimmer) (1.17 g, 1.83 mmol, 1.09 mL, 50% purity, 1.5 eq) and diisopropylethylamine (473.54 mg, 3.66 mmol, 638.20). μL, 3 eq) was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, water (10 mL) / ethyl acetate (10 mL) was added to the reaction system to dilute the mixture, the layers were separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1) to obtain the target compound WX109-2.

Step 2: Synthesis of compound WX109-3 WX109-2 (220 mg, 569.67 μmol, 1 eq), BB-3 (302.63 mg, 683.60 μmol, 1.2 eq) and potassium acetate (167.72) in a pre-dried 40 mL reaction bottle. mg, 1.71 mmol, 3 eq) was added, followed by dioxane (6 mL) and water (0.5 mL). It was then replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (41.68 mg, 56.97 μmol, 0.1 eq) was added, and the mixture was further replaced with nitrogen gas. The reaction was stirred at 90 ° C. for 12 hours. After completion of the reaction, water (10 mL) / ethyl acetate (10 mL) was added to the reaction system to dilute the mixture, the layers were separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). The organic phases were combined, washed with saturated brine (20 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give a residue. The crude product was purified by thin layer chromatography silica gel plate (methylene chloride: methanol = 20: 1) to obtain the target compound WX109-3.

Step 3: Synthesis of compounds WX109, WX110, WX111, WX112
WX109-3 was separated by an SFC separation chromatography column (Chiralpak IC-H 250 * 30 mm 5 μm; mobile phase: [MeOH]; B%: 45% -45%, 9 min) and the target compound WX109 (retention time: 2.18). min) and WX110 (holding time: 3.28 min) were obtained. WX109: 1H NMR (400MHz, CHLOROFORM-d) δ = 8.29 (s, 1H), 8.17 --8.08 (m, 3H), 7.98 (d, J = 2.0 Hz, 1H), 7.87 --7.83 (m, 1H), 7.82 --7.75 (m, 1H), 7.58 (s, 1H), 7.29 --7.25 (m, 1H), 7.17 --7.08 (m, 1H), 6.00 (br s, 1H), 4.21 (br dd, J = 4.8) , 13.2 Hz, 1H), 4.10 --4.03 (m, 1H), 4.00 (s, 3H), 3.30 (br s, 1H), 3.12 --3.01 (m, 1H), 1.83 --1.74 (m, 1H), 1.34 (br d, J = 6.9 Hz, 3H), 1.23 --1.13 (m, 1H), 1.17 (ddd, J = 4.8, 9.3, 14.0 Hz, 1H). WX110: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.32 --8.24 (m, 1H), 8.15 --8.07 (m, 3H), 7.96 (d, J = 2.2 Hz, 1H), 7.85 --7.81 (m,) 1H), 7.79 --7.75 (m, 1H), 7.54 (s, 1H), 7.25 --7.23 (m, 1H), 7.14 --7.07 (m, 1H), 6.01 (br s, 1H), 4.16 --4.10 (m) , 1H), 4.09 --4.01 (m, 1H), 3.96 (s, 3H), 3.32 --3.19 (m, 1H), 3.09 --2.98 (m, 1H), 1.91 --1.69 (m, 1H), 1.31 --1.24 (m, 3H), 1.30 --1.24 (m, 1H). The residue was recovered and further separated by an SFC separation chromatography column (OJ (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ MeOH]; B%: 35% -35%, 4 min). , WX111 (holding time: 2.38 min) and WX112 (holding time: 2.60 min) were obtained. WX111: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.27 (d, J = 2.2 Hz, 1H), 8.15 --8.08 (m, 2H), 8.06 (s, 1H), 7.95 (d, J = 2.4 Hz) , 1H), 7.84 --7.80 (m, 1H), 7.78 --7.73 (m, 1H), 7.54 (s, 1H), 7.26 --7.24 (m, 1H), 7.10 (ddd, J = 2.4, 7.5, 8.8 Hz) , 1H), 5.94 (br s, 1H), 4.17 (dd, J = 5.1, 13.2 Hz, 1H), 4.09 --3.99 (m, 1H), 3.98 --3.96 (m, 3H), 3.33 --- 3.20 (m, 1H), 3.08 --2.96 (m, 1H), 1.73 --1.67 (m, 1H), 1.30 (d, J = 6.8 Hz, 3H), 1.19 --1.07 (m, 1H), 1.12 (dq, J = 5.2, 9.6 Hz, 1H). WX112: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.32 --8.24 (m, 1H), 8.15 --8.07 (m, 3H), 7.96 (d, J = 2.2 Hz, 1H), 7.85 --7.81 (m,) 1H), 7.79 --7.75 (m, 1H), 7.54 (s, 1H), 7.25 --7.23 (m, 1H), 7.14 --7.07 (m, 1H), 6.01 (br s, 1H), 4.16 --4.10 (m) , 1H), 4.09 --4.01 (m, 1H), 3.96 (s, 3H), 3.32 --3.19 (m, 1H), 3.09 --2.98 (m, 1H), 1.91 --1.69 (m, 1H), 1.31 --1.24 (m, 3H), 1.30 --1.24 (m, 1H).

Example 63: WX113, WX114

Step 1: Synthesis of compound WX113-2.
Raw material WX113-1 (5 g, 22.93 mmol) and solvent N, N-dimethylformamide (30 mL) were added to a pre-dried three-necked flask, the temperature was lowered to 0 ° C., and sodium hydrogen hydrogen (605.42 mg, 25.23 mmol) was added. It was added and stirred for 30 minutes, and methyl iodide (3.58 g, 25.23 mmol, 1.57 mL) was further added and stirred for 30 minutes. Detected by thin layer chromatography (petroleum ether: ethyl acetate = 5: 1), and after completion of the reaction, water (20 mL) was added to the reaction solution and extracted with methylene chloride (20 mL * 3) to obtain the obtained organic phase. Is dried over anhydrous sodium sulfate and then dried under reduced pressure with a pump to obtain a crude product, which is separated and purified by preparative thin layer chromatography (petroleum ether: ethyl acetate = 4: 1) to obtain the target product. Obtained WX113-2. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.55 (d, J = 2.2 Hz, 1H), 8.47 (d, J = 2.2 Hz, 1H), 3.17 (d, J = 4.9 Hz, 4H), 3.20 --3.15 (m, 1H).

Step 2: Synthesis of compound WX113-3.

Raw material WX113-2 (3.1 g, 13.36 mmol), ammonium chloride (8.58 g, 160.32 mmol, 5.61 mL) and solvent methanol (30 mL), water (10 mL) were added to a pre-dried bite flask, followed by Zinc powder (6.12 g, 93.52 mmol) was added, and the mixture was further stirred at 25 ° C. for 2 hours. According to thin layer chromatography detection (petroleum ether: ethyl acetate = 1: 1), the raw materials disappeared and new products were released. Shown that it was generated. Water (10 mL) was added to the reaction solution, extracted with methylene chloride (20 mL × 2), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary-dried under reduced pressure with a pump to obtain a crude product. .. .. The little gift was purified by Prep-TLC (petroleum ether: ethyl acetate = 1: 1) to give the target product WX113-3. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.81 (d, J = 2.0 Hz, 1H), 6.96 (d, J = 2.2 Hz, 1H), 3.24 (br s, 2H), 2.99 (s, 4H).

Step 3: Synthesis of compound WX113-5 Raw material WX113-3 (2.2 g, 10.89 mmol), raw material WX113-4 (2.49 g, 10.89 mmol, 1.59 mL) and solvent pyridine (15 mL) are placed in a pre-dried reaction bottle. It was added and further stirred at 25 ° C. for 12 hours. Thin-layer chromatography detection (petroleum ether: ethyl acetate = 3: 1) showed that the raw material had disappeared and a new product had been produced. Water (10 mL) was added to the reaction solution, extracted with methylene chloride (15 mL * 3), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary-dried under reduced pressure with a pump to obtain a crude product. .. The little gift was purified by Prep-TLC (petroleum ether: ethyl acetate = 3: 1) to give the target product WX113-5. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.08 (d, J = 2.4 Hz, 1H), 7.97 (dd, J = 5.7, 9.0 Hz, 1H), 7.40 (dd, J = 2.4, 7.9 Hz, 1H) , 7.13 (ddd, J = 2.4, 7.4, 8.9 Hz, 1H), 6.85 (d, J = 2.2 Hz, 1H), 6.39 (br s, 1H), 5.45 (br s, 1H), 2.98 (s, 4H) ), 3.00 --2.96 (m, 1H), 3.00 --2.96 (m, 1H), 3.00 --2.96 (m, 1H).

Step 4: Synthesis of compound WX113-6 Raw material WX034-1 (1.33 g, 4.10 mmol) and solvent 1,4-dioxane (13 mL) are added to a pre-dried reaction bottle, followed by potassium acetate (805.31 mg, 8.21 mmol), bis (pinacolato) diboron (1.15 g, 4.51 mmol) was added and replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (300.20 mg, 410.28). μmol) was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 100 ° C. for 3 hours. After completion of the reaction, the reaction was directly applied to the next reaction to obtain the target product WX113-6 without post-treatment.

Step 5: Synthesis of Compound WX113-7 WX113-5 (1.5 g, 4.04 mmol), WX113-6 (1.75 g, 4.44 mmol) and potassium acetate (396.54 mg, 4.04 mmol) were added to a pre-dried flask. It was then dissolved in water (2 mL), 1,4-dioxane (20 mL). It was replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (295.65 mg, 404.05 μmol) was added, and the mixture was further replaced with nitrogen gas. The reaction was stirred at 80 ° C. for 24 hours. According to TLC (petroleum ether: ethyl acetate = 1: 1), the raw materials did not disappear and new points were created. Direct spin drying and no other post-treatment. The crude product was purified by column chromatography separation (petroleum ether: ethyl acetate = 1: 0 to 1: 1) to obtain a crude product, and purified by preparative HPLC to obtain the target product WX113-7. It was.

Step 6: Synthesis of compounds WX113 and WX114
WX113-7 (0.15 g, 268.33 μmol) is SFC (chromatography column: Chiralpak AD-H 250 * 30 mm id 5 μm; mobile phase: A: CO2, B: IPA (0.1% NH ₃ H ₂ O); gradient: B % = 35%; Flow velocity: 62 g / min; Wavelength: 220 nm; Column temperature: 40 ° C.) to obtain compounds WX113 (Rt = 1.556 min) and WX114 (Rt = 2.111 min). WX113: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.15 --8.12 (m, 2H), 8.12 --8.06 (m, 1H), 8.09 (dd, J = 5.8, 8.9 Hz, 1H), 7.98 (br s) , 1H), 7.84 (dd, J = 2.1, 8.5 Hz, 1H), 7.69 (d, J = 8.6 Hz, 1H), 7.49 (dd, J = 2.4, 8.6 Hz, 1H), 7.36 (d, J = 2.0 Hz, 1H), 7.28 --7.20 (m, 1H), 4.23 (dd, J = 5.0, 13.3 Hz, 1H), 4.01 (dd, J = 9.9, 13.5 Hz, 1H), 3.35 --3.25 (m, 14H) ), 3.00 (s, 3H), 2.62 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H). WX114: 1H NMR (400MHz, METHANOL-d4) δ = 8.14 (s, 1H), 8.11 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 5.6, 8.9 Hz, 1H), 7.98 (br d) , J = 15.4 Hz, 1H), 7.81 (dd, J = 2.3, 8.5 Hz, 1H), 7.68 (d, J = 8.6 Hz, 1H), 7.51 (dd, J = 2.6, 8.4 Hz, 1H), 7.36 (d, J = 2.2 Hz, 1H), 7.24 (dt, J = 2.6, 8.4 Hz, 1H), 4.21 (dd, J = 4.9, 13.5 Hz, 1H), 4.00 (dd, J = 9.9, 13.5 Hz, 1H), 3.01 (s, 3H), 2.99 --2.92 (m, 1H), 2.64 --2.56 (m, 3H), 1.31 --1.26 (m, 1H), 1.32 --1.26 (m, 1H), 1.32 --1.26 ( m, 1H), 1.23 ―― 1.19 (m, 1H), 1.23 ―― 1.19 (m, 1H), 1.23 ―― 1.19 (m, 1H), 1.36 ―― 1.19 (m, 1H), 1.24 ―― 1.17 (m, 1H), 1.24 --1.17 (m, 1H)
Example 64: WX115, WX116, WX117, WX118

Step 1: Synthesis of compound WX115-2 Compound WX024-1 (0.5 g, 1.61 mmol), compound WX115-1 (2 M, 964.22 μL, hydrochloric acid) and methylene chloride (25 mL) in a pre-dried bite flask (100 mL). ) In order, followed by N, N, diisopropylethylamine (623.08 mg, 4.82 mmol, 839.73 μL) and 1-propanephosphonic acid anhydride (cyclic trimmer) 50% ethyl acetate solution (1.23 g, 1.93 mmol, 1.15 mL). , 50% purity) was added. It was then replaced with nitrogen gas and stirred at 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried under reduced pressure and further purified by column chromatography separation (petroleum ether: ethyl acetate = 5: 1 to 0: 1) to obtain compound WX115-2. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.46 --8.30 (m, 1H), 8.16 --8.07 (m, 1H), 7.82 (dd, J = 2.3, 8.6 Hz, 1H), 7.64 --7.55 (m, 1H) ), 5.86 --5.52 (m, 1H), 4.28 --4.08 (m, 1H), 4.06 --3.82 (m, 1H), 3.05 --2.57 (m, 1H), 2.30 (quind, J = 3.4, 7.0 Hz, 1H) ), 1.34 --1.21 (m, 3H), 1.03 (t, J = 6.0 Hz, 3H), 0.76 --0.58 (m, 1H), 0.56 --0.38 (m, 2H).

Step 2: Synthesis of compound WX115-3 Compound WX115-2 (0.517 g, 1.42 mmol), compound BB-3 (628.37 mg, 1.42 mmol), potassium acetate (417.90 mg, 4.26) in a pre-dried reaction bottle (10 mL). mmol), solvent 1,4-dioxane (2 mL) and water (0.2 mL) were added in that order. Then, after replacement with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (103.86 mg, 141.94 μmol) was added, further replaced with nitrogen gas, and heated to 90 ° C. The mixture was stirred for 5 hours. After completion of the reaction, the reaction solution is cooled, filtered, and the filtrate is distilled under reduced pressure to remove the solvent, and then purified by column chromatography separation (petroleum ether: ethyl acetate = 5: 1 to 0: 1). Then, the compound WX115-3 was obtained. 1H NMR (400MHz, METHANOL-d4) δ = 8.32 (t, J = 1.8 Hz, 1H), 8.22 (d, J = 2.3 Hz, 1H), 8.18 (d, J = 2.4 Hz, 1H), 8.10 (dd) , J = 5.8, 8.8 Hz, 1H), 8.05 --7.98 (m, 2H), 7.77 (dd, J = 2.0, 8.5 Hz, 1H), 7.48 (dd, J = 2.5, 8.4 Hz, 1H), 7.28- 7.19 (m, 1H), 4.29 --4.18 (m, 1H), 4.00 (dd, J = 10.2, 13.3 Hz, 1H), 3.87 (s, 3H), 3.00 --2.85 (m, 1H), 2.23 (td, td, J = 3.7, 7.2 Hz, 1H), 1.24 --1.18 (m, 3H), 0.99 (t, J = 6.3 Hz, 3H), 0.71 --0.52 (m, 1H), 0.49 --0.33 (m, 2H).

Step 3: Synthesis of Compounds WX115, WX116, WX117, WX118 Compound WX115-3 (0.8 g, 1.33 mmol) is SFC (1: Chromato Column: OJ (250 mm * 30 mm, 5 μm); Mobile Phase: [MeOH]; B %: 30% -30%, 7min; 2: Chromato column: OJ (250mm * 30mm, 5μm); Mobile phase: [MeOH]; B%: 30% -30%, 5min; 3: Chromato column: OJ (250mm * 30mm, 5μm); Mobile phase: [MeOH]; B%: 30% -30%, 5min; Chromatography column: Chiralpak IC-H 250 * 30mm 5μm; Mobile phase: [0.1% NH ₃ H ₂ O Separated by B%: 45% -45%, 13min), WX115 (holding time: 2.852min), WX116 (holding time: 2.43min), WX117 (holding time: 3.96min), WX118 (holding time: 3.96min) : 4.89 min) was obtained. WX115: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.29 (d, J = 2.0 Hz, 1H), 8.19 --8.14 (m, 2H), 8.11 (dd, J = 5.8, 8.9 Hz, 1H), 7.99 (dd, J = 2.1, 8.5 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 2.5, 8.5 Hz, 1H) ), 7.23 (dt, J = 2.5, 8.3 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 3.99 (dd, J = 10.0, 13.3 Hz, 1H), 3.87 (s, 3H) , 3.00 --2.84 (m, 1H), 2.23 (td, J = 3.6, 7.3 Hz, 1H), 1.21 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H), 0.57 ( qt, J = 6.1, 9.2 Hz, 1H), 0.47 --0.34 (m, 2H). WX116: ¹ HNMR (400MHz, METHANOL-d4) δ = 8.29 (d, J = 2.0 Hz, 1H), 8.19 --8.14 (m, 2H), 8.11 (dd, J = 5.8, 8.9 Hz, 1H), 7.99 ( dd, J = 2.1, 8.5 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 2.5, 8.5 Hz, 1H), 7.23 (dt, J = 2.5, 8.3 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 3.99 (dd, J = 10.0, 13.3 Hz, 1H), 3.87 (s, 3H), 3.00 --2.84 (m, 1H), 2.23 (td, J = 3.6, 7.3 Hz, 1H), 1.21 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H), 0.57 (qt, J = 6.1, 9.2 Hz, 1H), 0.47 --0.34 (m, 2H). WX117: ¹ HNMR (400MHz, METHANOL-d4) δ = 8.29 (d, J = 2.0 Hz, 1H), 8.19 --8.14 (m, 2H), 8.11 (dd, J = 5.8, 8.9 Hz, 1H), 7.99 ( dd, J = 2.1, 8.5 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 2.5, 8.5 Hz, 1H), 7.23 (dt, J = 2.5, 8.3 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 3.99 (dd, J = 10.0, 13.3 Hz, 1H), 3.87 (s, 3H), 3.00 --2.84 (m, 1H), 2.23 (td, J = 3.6, 7.3 Hz, 1H), 1.21 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H), 0.57 (qt, J = 6.1, 9.2 Hz, 1H), 0.47 --0.34 (m, 2H). WX118: ¹ HNMR (400MHz, METHANOL-d4) δ = 8.29 (d, J = 2.0 Hz, 1H), 8.19 --8.14 (m, 2H), 8.11 (dd, J = 5.8, 8.9 Hz, 1H), 7.99 ( dd, J = 2.1, 8.5 Hz, 1H), 7.95 (d, J = 2.2 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.45 (dd, J = 2.5, 8.5 Hz, 1H), 7.23 (dt, J = 2.5, 8.3 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 3.99 (dd, J = 10.0, 13.3 Hz, 1H), 3.87 (s, 3H), 3.00 --2.84 (m, 1H), 2.23 (td, J = 3.6, 7.3 Hz, 1H), 1.21 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 6.2 Hz, 3H), 0.57 (qt, J = 6.1, 9.2 Hz, 1H), 0.47 --0.34 (m, 2H)
Example 65: WX119, WX120

Step 1: Synthesis of compound WX119-2 Compound WX119-1 (5 g, 21.06 mmol) and dimethylamine hydrochloride (3.43 g, 42.12 mmol, 1.28 mL, hydrochloric acid) are added in order to a pre-dried bite flask (100 mL). did. It was then replaced with nitrogen gas and stirred at 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was extracted with saturated sodium bicarbonate (100 mL) and methylene chloride (50 mL × 3), the organic phases were combined, washed with saturated sodium chloride, dried over anhydrous sodium sulfate, filtered, and filtered. Finally, it was dried under reduced pressure to obtain the target compound WX119-2, which was used as it was in the next step. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.33 (d, J = 2.3 Hz, 1H), 8.24 (d, J = 2.3 Hz, 1H), 3.05 (s, 6H).

Step 2: Synthesis of Compound WX119-3 Compound WX119-2 (4.5 g, 18.29 mmol), ammonium chloride (11.74 g, 219.46 mmol), methanol (180 mL) and water (90 mL) in a pre-dried three-necked flask (500 mL). mL) was added in sequence, and finally zinc powder (8.37 g, 128.02 mmol) was added slowly, then replaced with nitrogen gas, and the mixture was stirred at 50 ° C. for 10 hours. After completion of the reaction, the reaction solution is filtered, washed with methanol (100 mL × 3), the filtrates are combined, dried under reduced pressure, and extracted with saturated sodium bicarbonate (100 mL) and methylene chloride (100 mL × 4). , Organic phases combined, washed with saturated sodium chloride, further dried over anhydrous sodium sulfate, filtered, and finally rotat-dried under reduced pressure and column chromatographic separation (petroleum ether: ethyl acetate = 100: 1-30: Purification according to 1) gave compound WX119-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.80 (d, J = 2.1 Hz, 1H), 7.04 (d, J = 2.1 Hz, 1H), 3.95 --3.74 (m, 2H), 2.75 (s, 6H) ).

Step 3: Synthesis of compound WX119-5 Compound WX119-3 (0.7 g, 3.24 mmol) and compound WX119-4 (742.04 mg, 3.24 mmol) are added in this order to a pre-dried reaction bottle (40 mL), and finally pyridine. (14 mL) was added. After that, it was replaced with nitrogen gas, heated to 20 ° C., and stirred for 5 hours. After completion of the reaction, the reaction mixture was spin-dried under reduced pressure, and further preparative HPLC (chromatography column: Agela Durashell C18 150 * 25 mm 5 μm; mobile phase: [water (10 mM NH ₄ HCO ₃ ) -ACN]; B% : 25% -60%, 10.5 min) to give compound WX119-5. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.20 (dd, J = 5.7, 8.8 Hz, 1H), 8.06 (d, J = 2.3 Hz, 1H), 7.72 (d, J = 2.1 Hz, 1H), 7.27 --7.23 (m, 1H), 7.17 (ddd, J = 2.5, 7.4, 8.9 Hz, 1H), 2.75 (s, 1H), 2.68 (s, 6H).

Step 4: Synthesis of compound WX119-6 Compound WX113-6 (687.75 mg, 1.85 mmol), compound WX119-5 (393 mg, 961.65 μmol), water (0.7 mL), 1 in a pre-dried reaction bottle (10 mL). , 4-Dioxane (7 mL) and potassium acetate (283.13 mg, 2.88 mmol) were added in sequence, followed by substitution with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II). ) Dichloride (70.36 mg, 96.16 μmol) was added. The mixture was further replaced with nitrogen gas, heated to 90 ° C., and stirred for 10 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent, and further purified by column chromatography separation (petroleum ether: ethyl acetate = 5: 1 to 0: 1). It was then purified by preparative HPLC. Purification method: Chromatography column: Xtimate C18 150 * 25mm * 5μm; Mobile phase: [Water (10mM NH ₄ HCO ₃ ) -ACN]; B%: 27% -47%, 10.5min. Compound WX119-6 was obtained. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.3 Hz, 1H), 8.19 --8.14 (m, 2H), 8.06 (dd, J = 5.8, 8.9 Hz, 1H), 7.87 (dd) , J = 2.3, 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.57 --7.50 (m, 2H), 7.31 --7.24 (m, 1H), 4.23 (dd, J = 5.0, 13.4) Hz, 1H), 4.02 (dd, J = 9.8, 13.4 Hz, 1H), 3.02 --2.91 (m, 7H), 2.65 --2.59 (m, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Step 5: Synthesis of compounds WX119 and WX120 Compound WX119-6 (0.22 g, 383.92 μmol, 1 eq) is SFC (Instrument: Thar SFC80 preparative SFC; chromatography column: Chiralpak AD-H 250 * 30 mm id 5 μ; mobile phase: A: CO2, B: IPA; Gradient: B% = 30%; Flow velocity: 65 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by compound WX119 (retention time:: 2.19 min) and WX120 (holding time: 2.34 min) were obtained. WX119: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.34 (d, J = 2.4 Hz, 1H), 8.20 --8.15 (m, 2H), 8.06 (dd, J = 5.8, 9.0 Hz, 1H), 7.88 (dd, J = 2.3, 8.5 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.57 --7.79 (m, 2H), 7.27 (dt, J = 2.6, 8.3 Hz, 1H), 4.24 (dd, J = 5.0, 13.3 Hz, 1H), 4.02 (dd, J = 9.9, 13.5 Hz, 1H), 2.95 (s, 7H), 2.62 (s, 3H), 1.24 (d, J = 6.9 Hz, 3H). WX120: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.34 (d, J = 2.4 Hz, 1H), 8.20 --8.15 (m, 2H), 8.06 (dd, J = 5.8, 9.0 Hz, 1H), 7.88 (dd, J = 2.3, 8.5 Hz, 1H), 7.72 (d, J = 8.7 Hz, 1H), 7.57 --7.79 (m, 2H), 7.27 (dt, J = 2.6, 8.3 Hz, 1H), 4.24 (dd, J = 5.0, 13.3 Hz, 1H), 4.02 (dd, J = 9.9, 13.5 Hz, 1H), 2.95 (s, 7H), 2.62 (s, 3H), 1.24 (d, J = 6.9 Hz, 3H)
Example 66: WX121, WX122

Step 1: Synthesis of compound WX121-2 Compound WX121-1 (20.00 g, 176.82 mmol) and potassium carbonate (23.22 g, 167.98 mmol) were dissolved in DMF (500.00 mL) and methyl iodide (23.84 g, 23.84 g,) at 0 ° C. 167.98 mmol) was added and stirred at 25 ° C. overnight. After completion of the reaction, the mixture was poured into water (500.00 mL) and extracted 3 times with methylene chloride (500 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtration to remove the desiccant, the solvent is removed under reduced pressure and the crude residue is purified by column chromatography (ethyl acetate / petroleum ether = 0% -10%) to give compound WX121-2. It was.

Step 2: Synthesis of Compound WX121-3 Compound WX121-2 (3.0 g, 23.60 mmol) is dissolved in methanol (25.00 mL), Runny Nickel (404.29 mg, 4.72 mmol) is added under nitrogen gas protection, and hydrogen is added. Gas (50 psi) was introduced and stirred at 30 ° C. overnight. After completion of the reaction, the solvent was removed under reduced pressure to obtain compound WX121-3. MS-ESI m / z: 133.1 [M + H] +.

Step 3: Synthesis of Compound WX121-5 Compound 2-amino-4-fluoro-5-bromobenzoic acid (356.81 mg, 1.52 mmol) was dissolved in N, N'-dimethylformamide (3.00 mL) and diisopropylethylamine (394.11). mg, 3.05 mmol), HATU (878.33 mg, 2.31 mmol) and WX121-3 (419.63 mg, 2.31 mmol) were added and stirred at 25 ° C. for 16 hours. After completion of the reaction, the mixture was poured into water (10 mL) and extracted 3 times with methylene chloride (10 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, the crude residue was separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1:30), and the target compound WX121-5 Got MS-ESI m / z: 349.0 [M + H] +, 351.0 [M + H + 2] +.

Step 4: Synthesis of compound WX121-6 Compound WX121-5 (200 mg, 576.07 μmol) is dissolved in ethanol (10.00 mL), formamidine acetate (299.87 mg, 2.88 mmol l) is added, and 2 at 80 ° C. Stirred for hours. After completion of the reaction, the organic solvent was spin-dried, poured into water (20 mL), and extracted 3 times with methylene chloride (20 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, and the crude residue was separated by a preparative chromatography plate (eluent: methanol / methylene chloride / triethylamine = 1: 20: 0.02) for the purpose. Compound WX121-6 was obtained. MS-ESI m / z: 359.0 [M + H] +, 361.0 [M + H + 2] +.

Step 5: Synthesis of compound WX121-7 Compound WX121-6 (0.19 g, 531.95 μmol), BB-2 (235.49 mg, 531.95 μmol), potassium acetate (208.82 mg, 2.13 mmol) was added to dioxane (2.00 mL) and water (2.00 mL). Dissolve in 0.20 mL), then add [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (7.78 mg, 10.64 μmol) and heat to 95 ° C under nitrogen gas protection 2 Stirred for hours. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (20.00 mL), and extracted 3 times with methylene chloride (20.00 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, and the residue was separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1:30) to obtain the target compound WX121-7. It was. MS-ESI m / z: 593.0 [M + H] +, 595.0 [M + H + 2] +.

Step 6: Synthesis of compound WX121-8
WX121-7 (0.1 g, 178.26 μmol) is dissolved in tetrahydrofuran (5.00 mL) and water (5.00 mL), lithium hydroxide monohydrate (56.61 mg, 1.35 mmol) is added thereto, and the reaction solution is 25 ° C. After the reaction was completed, the reaction solution was rotated and dried, water (10 mL) was added thereto, the mixture was washed 3 times with methylene chloride (10 mL), and concentrated hydrochloric acid (0.20 mL) was added to the aqueous phase. The mixture was added dropwise, extracted 3 times with methylene chloride (5 mL), washed with organic phase saturated brine (10.00 mL), dried over anhydrous sodium sulfate, and the organic phase was rotationally dried to obtain the target compound WX121-8. It was. MS-ESI m / z: 565.0 [M + H] +, 567.0 [M + H + 2] +.

Step 7: Synthesis of compound WX121-9 Compound WX121-8 (150 mg, 265.51 μmol) was dissolved in DMF (3.00 mL), and triethylamine (53.73 mg, 531.02 μmol) and HATU (100.96 mg, 265.51 μmol), methylamine. Hydrochloride (17.93 mg, 265.51 μmol) was added and stirred at 30 ° C. for 2 hours. After completion of the reaction, the solvent was removed under reduced pressure, the mixture was poured into water (5 mL), and the mixture was extracted 3 times with methylene chloride (10 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent is removed under reduced pressure, the crude residue is separated by a preparative chromatography plate (eluent: methanol / methylene chloride = 1:15), and further an HPLC preparative column. Separation by (water s Xbridge 150 * 25 5u; mobile phase: [water (10 mM NH4HCO3) -ACN]; B%: 26% -56%, 7 min) gave the target compound WX121-9. MS-ESI m / z: 578.0 [M + H] ⁺ , 580.0 [M + H + 2] ⁺ .

Step 8: Synthesis of Compounds WX121 and WX122 Compound WX121-9 is supercritical fluid chromatography (separation condition column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B%: Separation by 55% -55%) gave enantiomers WX121 and WX122. The retention times were 0.626 min and 1.531 min, respectively, and the proportion was 1: 1. WX121: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.14 (d, J = 8.3 Hz, 1H), 8.10 --8.01 (m, 2H), 7.97 (s, 1H), 7.85 (br s, 1H), 7.36 (d, J = 11.3 Hz, 1H), 7.18 (br s, 1H), 7.06 (br t, J = 7.3 Hz, 1H), 5.58 (br s, 1H), 4.18 --4.04 (m, 1H), 4.02 --3.83 (m, 4H), 2.97 --2.79 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 1.27 --1.20 (m, 3H). WX122: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.14 (d, J = 8.3 Hz, 1H), 8.12-8.01 (m, 2H), 7.96 (s, 1H), 7.85 (br s, 1H), 7.37 (d, J = 11.0 Hz, 1H), 7.17 (br s, 1H), 7.06 (br t, J = 7.0 Hz, 1H), 5.55 (br s, 1H), 4.18 --4.03 (m, 1H), 4.01 --3.81 (m, 4H), 2.96 --2.79 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 1.21 (br d, J = 7.0 Hz, 3H).

Example 67: WX123, WX124

Step 1: Synthesis of compound WX123-2
WX123-1 (3 g, 19.34 mmol) and NBS (3.44 g, 19.34 mmol) were added to methylene chloride (60 mL) and reacted at 25 ° C. for 2 hours. After completion of the reaction, the reaction solution was filtered, the cake was washed with methylene chloride (100 mL), and then the cake was dried to obtain the target compound WX123-2, which was used as it was in the next reaction. ^{1 1} H NMR (400MHz, DMSO-d6) δ = 6.54 --6.58 (m, 1H), 7.37 --7.42 (m, 1H).
Step 2: Synthesis of compound WX123-3
X123-2 (2 g, 8.55 mmol), WX121-3 (1.68 g, 12.82 mmol), EDCI (1.67 g, 8.72 mmol), TEA (3.46 g, 34.18 mmol, 4.76 mL), 1-oxide pyridine-1- Ium-2-ol (1.11 g, 10.00 mmol) was added to DCM (50 mL) and reacted at 50 ° C. for 16 hours. After completion of the reaction, the reaction mixture was spin-dried, diluted with water (100 mL), extracted with DCM (100 mL), the organic phase was spin-dried, and column chromatography (ethyl acetate: petroleum ether = 0% to 20%). The target compound WX123-3 was obtained by separation and purification. MS-ESI m / z: 346.9 [M + H] ⁺ , 348.9 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX123-4
WX123-3 (0.72 g, 1.59 mmol) and lithium hydroxide monohydrate (0.668 g, 15.92 mmol) were added to EtOH (10 mL) and H ₂ O (10 mL) and reacted at 25 ° C. for 16 hours. It was. After completion of the reaction, the reaction solution was spin-dried, extracted with DCM (50 mL), and the aqueous phase was spin-dried to obtain the target compound WX123-4, which was used as it was in the next reaction. MS-ESI m / z: 318.9 [M + H] ⁺ , 320.9 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX123-5
WX123-4 (0.9 g, 2.82 mmol) and formamidine acetate (585.00 mg, 5.62 mmol) were added to EtOH (80 mL) and reacted at 80 ° C. for 48 hours. After completion of the reaction, the reaction solution was spin-dried, diluted with water (100 mL), extracted with DCM (100 mL × 3), and the organic phase was spin-dried to obtain the target compound WX123-5. MS-ESI m / z: 328.8 [M + H] ⁺ , 330.8 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX123-6
Add WX123-5 (0.4 g, 418.93 μmol), methylamine (0.084 g, 1.24 mmol, HCl), HATU (0.26 g, 683.80 μmol), DIEA (163.24 mg, 1.26 mmol, 0.22 mL) to DMF (5 mL). It was added and reacted at 20 ° C. for 16 hours. After completion of the reaction, the reaction mixture is spin-dried, diluted with water (50 mL), extracted with DCM (50 mL), the organic phase is spin-dried, and further by column chromatography (EA: PE = 0% -80%). The mixture was separated and purified to obtain the target compound WX123-6. MS-ESI m / z: 341.9 [M + H] ⁺ , 343.9 [M + H + 2] ⁺ .

Step 6: Synthesis of compound WX123-7
Dioxane (5 mL) containing WX123-6 (0.18 g, 305.07 μmol ₎ , BB-3 (0.143 g, 304.19 μmol), Pd (dppf) Cl ₂ (0.022 g, 30.07 μmol), KOAc (0.12 g, 1.22 mmol) And added to water (1 mL), the system was replaced 3 times with N ₂ and then reacted at 105 ° C. for 1 hour under N 2 protection. After completion of the reaction, the reaction mixture was rotationally dried, diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was rotationally dried, and the preparative HPLC (chromatography column: Xtimate C18 150 * 25 mm * 5 μm; Mobile phase: [Water (0.225% FA) -ACN]; B%: 40% -50%, 9.5 min) was separated and purified to obtain the target compound WX123-7. Step 7: Synthesis of compounds WX123 and WX124
WX123-7 is separated by SFC (chromatography column: OJ (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 40%-%) and enantiomer WX123 (rt = 4.531 min) and WX124 (rt = 5.318 min) were obtained. WX123: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.25 (br s, 1 H), 8.14 --8.25 (m, 2 H), 7.85 --8.00 (m, 3 H), 7.69 --7.82 (m) , 2 H), 7.56 (br d, J = 8.5 Hz, 1 H), 7.36 (br t, J = 7.3 Hz, 1 H), 3.86 --4.09 (m, 2 H), 3.71 (s, 3 H) , 2.85 (br d, J = 7.5 Hz, 1 H), 2.47 --2.49 (m, 3 H), 1.08 (br d, J = 7.0 Hz, 3 H), MS-ESI m / z: 578.0 [M + H] ⁺ . WX124: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.14 --10.41 (m, 1 H), 8.19 (s, 2 H), 7.86 --7.97 (m, 3 H), 7.78 (s, 1 H) ), 7.73 (dd, J = 8.5, 2.5 Hz, 1 H), 7.57 (d, J = 8.5 Hz, 1 H), 7.36 (td, J = 8.4, 2.8 Hz, 1 H), 3.87 --4.09 (m) , 2 H), 3.71 (s, 3 H), 2.84 (br dd, J = 15.1, 6.5 Hz, 1 H), 2.53 (d, J = 2.0 Hz, 3 H), 1.08 (d, J = 7.0 Hz) , 3 H), MS-ESI m / z: 578.0 [M + H] ⁺ .

Example 68: WX125, WX126

Step 1: Synthesis of compound WX125-3.

Add raw material lithium diisopropylamide (2 M, 76.85 mL, 2 eq, 77 mL) to a pre-dried three-necked flask, allow to cool to -78 ° C, and tetrahydrofuran (20 mL) of WX125-1 (10 g, 96.06 mmol). The solution was added dropwise and the mixture was stirred at −78 ° C. for 1 hour. The mixture was maintained at -78 ° C, WX125-2 (15.47 g, 192.12 mmol, 14.59 mL) was added, the reaction system was further heated to -40 ° C, maintained at -40 ° C, and stirred for 3 hours. After completion of the reaction, a saturated ammonium chloride solution was added for quenching, and the mixture was further extracted with methylene chloride (10 mL × 3). The obtained organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure with a pump, and flushed. Purification by column chromatography separation (petroleum ether: ethyl acetate = 1: 0) gave the target product WX125-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 3.96 (br d, J = 6.0 Hz, 1H), 3.98 --3.92 (m, 1H), 3.98 --3.92 (m, 1H), 3.91 (br s, 1H) , 3.94 --3.85 (m, 1H), 3.94 --3.85 (m, 1H), 3.77 --3.65 (m, 5H), 3.41 --3.34 (m, 3H), 2.87 (quin, J = 5.8 Hz, 1H), 2.64 --2.55 (m, 1H), 1.45 --1.44 (m, 1H), 1.45 --1.44 (m, 1H), 1.46 (d, J = 6.4 Hz, 2H).

Step 2: Synthesis of compound WX125-4.

Raw material WX125-3 (4.07 g, 27.47 mmol, 1 eq) and solvent methylene chloride (40 mL) were added to a pre-dried bite flask, followed by triethylamine (6.95 g, 68.68 mmol, 9.56 mL). The temperature was lowered to 0 ° C., Tert-butyldiphenylchlorosilane (4.97 g, 32.97 mmol, 4.04 mL) was added slowly, and the mixture was further stirred at 25 ° C. for 12 hours. According to thin layer chromatography detection (petroleum ether: ethyl acetate = 10: 1), it was shown after the reaction was completed, water (20 mL) was added to the system, and the mixture was extracted with methylene chloride (20 mL × 3). The phase was dried over anhydrous sodium sulfate and then dried under reduced pressure with a pump to give a crude product. The crude product was purified by column chromatography separation (petroleum ether: ethyl acetate = 1: 0-30: 1) to give the target product WX125-4. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 3.86 --3.82 (m, 2H), 3.71 (s, 3H), 3.66 --3.58 (m, 2H), 3.35 (s, 3H), 2.86 --2.81 (m,) 1H), 0.92 (s, 14H), 0.88 (s, 11H), 0.13 --0.12 (m, 1H), 0.12 --0.09 (m, 8H), 0.05 (s, 5H).

Step 3: Synthesis of compound WX125-5.

Raw material WX125-4 (1.38 g, 5.26 mmol) was added to a pre-dried reaction bottle, followed by nitromethane (3.27 g, 105.18 mmol), and the mixture was further stirred at 50 ° C. for 12 hours. According to TLC (petroleum ether / ethyl acetate = 3/1), it was shown that the raw material was completely consumed and new points were created. The reaction mixture was spin-dried and purified by column chromatography separation (petroleum ether: ethyl acetate = 5: 1 to 1: 1) to obtain the target compound WX125-5. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 6.48 (br s, 1H), 3.83 --3.69 (m, 2H), 3.61 --3.45 (m, 2H), 3.28 (s, 3H), 2.73 (d, J) = 4.8 Hz, 3H), 2.54 (quin, J = 6.2 Hz, 1H), 0.86-0.78 (m, 9H), 0.00 (s, 6H).

Step 4: Synthesis of compound WX125-6.

Compounds WX125-5 (0.5 g, 1.91 mmol) and tetrahydrofuran (5 mL) were added sequentially to a pre-dried reaction bottle (40 mL), and finally tetrabutylammonium fluoride (1 M, 1.91 mL) was added. It was then replaced with nitrogen gas and stirred at 25 ° C. for 3 hours. According to TLC (petroleum ether / ethyl acetate = 3/1), it was shown that the reaction was completed. The reaction mixture was spin-dried under reduced pressure to obtain the target compound WX125-6, which was used as it was in the next reaction.

Step 5: Synthesis of compound WX125-7.

Compound WX125-6 (0.7 g, 4.72 mmol), triethylamine (717.14 mg, 7.09 mmol, 986.44 μL) and methylene chloride (7 mL) were added in this order to a pre-dried reaction bottle (8 mL), and finally at 0 ° C. Methanesulfonyl chloride (649.46 mg, 5.67 mmol, 438.83 μL) was added. After that, the mixture was replaced with nitrogen gas, the temperature was slowly raised to 25 ° C., and the mixture was stirred for 3 hours. After completion of the reaction, the reaction mixture was spin-dried under reduced pressure and then purified by preparative TLC (ethyl acetate) to give the target product WX125-7. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 6.37 (br s, 1H), 4.57 --4.38 (m, 2H), 3.69 --3.55 (m, 2H), 3.46 --3.33 (m, 3H), 3.05 (s) , 3H), 2.93 --2.76 (m, 4H).

Step 6: Synthesis of compound WX125-8.

Compound BB-1 (0.28 g, 1.24 mmol), compound WX125-7 (280.27 mg, 1.24 mmol), potassium iodide (20.65 mg, 124.42 μmol), potassium carbonate (343.92 mg) in a pre-dried reaction bottle (8 mL). , 2.49 mmol) were added in sequence, and finally N, N-dimethylformamide (3 mL) was added. After that, it was replaced with nitrogen gas, heated to 70 ° C., and stirred for 24 hours. After completion of the reaction, the reaction solution was cooled, rotated dry under reduced pressure, and purified by preparative HPLC to obtain the target compound WX125-8. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 7.84 (dd, J = 2.3, 8.7 Hz, 1H), 7.60 (d, J = 8.6 Hz, 1H), 6.23 (br s, 1H), 4.28 --4.13 (m, 2H), 3.68 --3.54 (m, 2H), 3.38 (s, 3H), 3.12 --3.02 (m, 1H), 2.78 (d, J = 4.9 Hz, 3H)
Step 7: Compound WX125-9
Compound WX125-8 (88.50 mg, 249.87 μmol), Compound BB-3 (110.62 mg, 249.87 μmol), KOAc (73.57 mg, 749.62 μmol) and solvent 1,4-dioxane (10 mL) in a pre-dried reaction bottle (10 mL). 2 mL) and water (0.2 mL) were added in that order. After that, it was replaced with nitrogen gas, then [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (18.28 mg, 24.99 μmol) was added, further replaced with nitrogen gas, and heated to 90 ° C. The mixture was stirred for 5 hours. After completion of the reaction, the reaction solution is cooled, filtered, and the filtrate is distilled under reduced pressure to remove the solvent, purified by preparative TLC (ethyl acetate), and further purified by preparative HPLC. Compound WX125-9 was obtained. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.33 (d, J = 2.2 Hz, 1H), 8.22 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.10 (dd, J = 5.8) , 8.9 Hz, 1H), 8.04 --7.99 (m, 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.27 --7.20 (m, 1H) , 4.39 (dd, J = 5.2, 13.6 Hz, 1H), 4.11 (dd, J = 9.2, 13.6 Hz, 1H), 3.87 (s, 3H), 3.66 --3.56 (m, 2H), 3.36 (s, 3H) ), 3.25 --- 3.18 (m, 1H), 2.64 (s, 3H).

Step 8: Compounds WX125 and WX126
WX125-9 was separated by SFC (chromatography column: OD (250 mm * 30 mm, 10 μm); mobile phase: [ETOH]; B%: 45% -45%, 6 min) and enantiomer WX125 (retention time: 2.689 min). ) And WX126 (holding time: 2.693 min) were obtained. WX125: 1H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (d, J = 2.0 Hz, 1H), 8.18 (s, 1H), 8.15 --8.11 (m, 2H), 7.98 (d, J = 2.2 Hz, 1H), 7.87 --7.83 (m, 1H), 7.80 --7.77 (m, 1H), 7.54 (br s, 1H), 7.60 --7.84 (m, 1H), 7.29 --7.27 (m, 1H), 7.29 --7.27 (m, 1H), 7.15 --7.09 (m, 1H), 6.25 (br d, J = 4.4 Hz, 1H), 4.30 --4.18 (m, 2H), 3.99 (s, 3H), 3.69 --3.57 (m, 2H), 3.40 (s, 3H), 3.15 --3.08 (m, 1H), 2.80 (d, J = 4.8 Hz, 3H). WX126: 1H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (d, J = 1.7 Hz, 1H), 8.18 (s, 1H), 8.16 --8.10 (m, 2H), 7.98 (s, 1H), 7.88- 7.82 (m, 1H), 7.81 --7.75 (m, 1H), 7.53 (br s, 1H), 7.29 --7.27 (m, 1H), 7.12 (br t, J = 7.0 Hz, 1H), 6.24 (br s) , 1H), 4.29 --4.18 (m, 2H), 3.99 (s, 3H), 3.70 --3.56 (m, 2H), 3.40 (s, 3H), 3.16 --3.08 (m, 1H), 2.80 (d, J) = 4.8 Hz, 3H).

Example 69: WX127

Step 1: Synthesis of compound WX127-2.

Compound WX127-1 (13.7 g, 67.49 mmol), hydrazine hydrate (4.14 g, 80.99 mmol, 4.02 mL, 98% purity) and tetrahydrofuran (140 mL) were added in that order to a pre-dried bite flask, and finally, Palladium carbon (1.71 g, 8.15 mmol) was added. It was then replaced with nitrogen gas and stirred at 25 ° C. for 3 hours. After completion of the reaction, the reaction solution was cooled and filtered, and the cake was washed with methanol (100 mL × 2) and then dried under reduced pressure to obtain a crude compound WX127-2. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.09 (d, J = 2.3 Hz, 1H), 8.03 (d, J = 1.9 Hz, 1H), 7.52 (t, J = 2.1 Hz, 1H)
Step 2: Synthesis of compound WX127-3.

Compound WX127-2 (5 g, 26.45 mmol), sodium chloroformate (2.67 g, 31.74 mmol, 1.23 mL), 4-dimethylaminopyridine (3.23 g, 26.45 mmol) and in a pre-dried bite flask (100 mL). Tetrahydrofuran (50 mL) was added in sequence, and finally methyl chloroformate (3.00 g, 31.74 mmol, 2.46 mL) was added. It was then replaced with nitrogen gas and stirred at 20 ° C. for 5 hours. After completion of the reaction, the reaction mixture was spin-dried under reduced pressure and purified by column chromatography separation (methylene chloride: methanol = 200: 1 to 20: 1) to obtain the target product WX127-3. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.72 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 1.8 Hz, 1H), 8.29 (s, 1H), 3.94 (s, 3H).

Step 3: Synthesis of compound WX127-5.

Compound WX127-3 (3 g, 12.14 mmol), compound WX127-4 (4.01 g, 12.14 mmol) and methylene chloride (121 mL) were added in this order to a pre-dried reaction bottle. It was then replaced with nitrogen gas and stirred at 20 ° C. for 10 hours. After completion of the reaction, the target compound was purified by distillation under reduced pressure to remove the solvent, purified by flash column chromatography separation (petroleum ether: ethyl acetate = 200: 1 to 30: 1), and further purified by preparative HPLC. Obtained WX127-5. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.66 (d, J = 1.9 Hz, 1H), 8.64 (d, J = 2.3 Hz, 1H), 7.92 (t, J = 2.1 Hz, 1H), 3.93 (s) , 3H).

Step 4: Synthesis of compound WX127-6.

Compound WX127-5 (0.35 g, 1.11 mmol) and nitromethane (11 mL) were added in order to the pre-dried microwave tube. It was then replaced with nitrogen gas and stirred in a microwave reactor at 160 ° C. (17 bar) for 1 hour. After completion of the reaction, the solvent was removed by distillation under reduced pressure, and purification was performed by preparative TLC (petroleum ether: ethyl acetate = 5: 1) to obtain the target product WX192-6. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.75 (br s, 1H), 7.99 (d, J = 2.3 Hz, 1H), 6.96 --6.86 (m, 1H), 3.85 (s, 3H).

Step 5: Synthesis of compound WX127-7.
Compound WX127-6 (0.16 g, 507.87 μmol), methanol (2 mL), water (0.4 mL), were added in this order to a pre-dried reaction bottle, and finally lithium hydroxide monohydrate (85.24 mg, 2.03). mmol) was added. After that, it was replaced with nitrogen gas, heated to 50 ° C., and stirred for 24 hours. After completion of the reaction, the reaction solution is cooled, distilled under reduced pressure to remove the solvent, then extracted with methylene chloride (10 mL × 3), combined with organic phases, and washed with saturated sodium chloride (10 mL). Then, it was further dried over anhydrous sodium sulfate, filtered, and finally rotary-dried under reduced pressure to obtain the target compound WX127-7. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.70 (d, J = 2.2 Hz, 1H), 7.21 (d, J = 2.2 Hz, 1H), 3.96 (s, 2H).

Step 6: Synthesis of compound WX127-9 Compound WX127-7 (110 mg, 428.00 μmol) and tetrahydrofuran (2 mL) are added in sequence to a pre-dried reaction bottle, followed by sodium hydrogen (34.24 mg, 856.01 μmol, 60). % Purity) was added slowly, and finally compound WX127-8 (147.05 mg, 642.00 μmol, 93.67 μL) was added dropwise. After that, it was replaced with nitrogen gas, and the mixture was stirred at 25 ° C. for 5 hours. After completion of the reaction, the reaction solution was spin-dried under reduced pressure and purified by preparative TLC (petroleum ether / ethyl acetate = 5/1) to obtain compound WX127-9. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.11 --8.06 (m, 2H), 8.04 (d, J = 2.2 Hz, 1H), 7.31 (dd, J = 2.5, 8.0 Hz, 1H), 7.17 --7.11 ( m, 1H).

Step 7: Synthesis of compound WX127.
Compound WX127-9 (0.1 g, 269.37 μmol), WX113-6 (53 mg, 117.88 μmol), water (0.2 mL), 1,4-dioxane (2 mL) and potassium acetate (79.31) in a pre-dried reaction bottle. mg, 808.11 μmol) were added in sequence, followed by replacement with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (19.71 mg, 26.94 μmol) was added. The mixture was further replaced with nitrogen gas, heated to 110 ° C., and stirred for 3 hours. After completion of the reaction, the solvent was removed by distillation under reduced pressure, purified by preparative TLC (methylene chloride / methanol = 10/1), and further purified by preparative HPLC to obtain the target product WX127. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.3 Hz, 1H), 8.19 --8.14 (m, 2H), 8.06 (dd, J = 5.8, 8.9 Hz, 1H), 7.87 (dd) , J = 2.3, 8.5 Hz, 1H), 7.71 (d, J = 8.5 Hz, 1H), 7.57 --7.50 (m, 2H), 7.31 --7.24 (m, 1H), 4.23 (dd, J = 5.0, 13.4) Hz, 1H), 4.02 (dd, J = 9.8, 13.4 Hz, 1H), 3.02 --2.91 (m, 7H), 2.65 --2.59 (m, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 70: WX128, WX129

Step 1: Synthesis of compound WX128-2 Raw material WX128-1 (5 g, 21.06 mmol), raw material 1,8-diazabicycloundec-7-ene (14.43 g, 94.76 mmol, 14.28) in a pre-dried bite flask. mL) and the solvent isopropanol (40 mL) were added, and the mixture was stirred at 25 ° C. for 12 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, extracted with methylene chloride (30 mL * 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then rotary-dried under reduced pressure to perform preparative thinning. Purification by layer chromatography (petroleum ether: ethyl acetate = 50: 1) gave the target compound WX128-2. ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.2 Hz, 1H), 8.33 (d, J = 2.4 Hz, 1H), 5.49 --5.45 (m, 1H).

Step 2: Synthesis of compound WX128-3 Raw material WX128-2 (1.9 g, 7.28 mmol) and solvent acetic acid (25 mL) are added to a pre-dried reaction bottle, followed by iron powder (4.06 g, 72.78 mmol). It was added and further stirred at 25 ° C. for 2 hours. After completion of the reaction, add a small amount of ethanol to the reaction solution to dilute it, filter it, add water (15 mL) to the filtrate, extract with methylene chloride (15 mL × 3), and extract the obtained organic phase with anhydrous sulfuric acid. After drying on sodium, the mixture was rotated and dried under reduced pressure and purified by flash column chromatography separation (petroleum ether: mobile phase ethyl acetate = 1: 0 to 10: 1) to obtain the target compound WX128-3. 1H NMR (400MHz, CHLOROFORM-d) δ = 7.56 (d, J = 2.2 Hz, 1H), 7.27 (s, 1H), 6.97 --6.96 (m, 1H), 6.97 (d, J = 2.2 Hz, 1H) , 5.28 (spt, J = 6.2 Hz, 1H), 1.36 (d, J = 6.2 Hz, 7H).

Step 3: Synthesis of compound WX128-4 In a pre-dried bite flask, raw material WX128-3 (1.42 g, 6.14 mmol), raw material 2-chloro-4-fluorobenzenesulfonyl chloride (1.83 g, 7.99 mmol, 1.17 mL) and The solvent pyridine (15 mL) was added, and the mixture was further stirred at 25 ° C. for 12 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with methylene chloride (10 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then rotary-dried under reduced pressure for flash column chromatography. Purification by chromatographic separation (petroleum ether: ethyl acetate = 1: 0 to 10: 1) gave the desired compound WX128-4. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.34 (dd, J = 5.7, 9.0 Hz, 1H), 8.26 (d, J = 2.3 Hz, 1H), 8.08 (dd, J = 5.7, 8.8 Hz, 1H) , 8.01 (d, J = 2.4 Hz, 1H), 7.86 --7.86 (m, 1H), 7.87 --7.84 (m, 1H), 7.49 (s, 1H), 7.25 --7.23 (m, 1H), 7.10 (ddd) , J = 2.5, 7.5, 8.8 Hz, 1H), 5.28 --5.23 (m, 1H), 1.29 (d, J = 6.1 Hz, 6H), 1.06 (d, J = 6.3 Hz, 1H).

Step 4: Synthesis of compound WX128-5 Raw material WX128-4 (300 mg, 708.07 μmol), raw material bis (pinacolato) diboron (179.81 mg, 708.07 μmol) and solvent 1,4-dioxane (3) in a pre-dried reaction bottle. mL) was added, followed by potassium acetate (138.98 mg, 1.42 mmol), replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (51.81 mg,). 70.81 μmol) was added, replaced with nitrogen gas, and further stirred at 90 ° C. for 3 hours. After completion of the reaction, the target compound WX128-5 was obtained and directly charged into the next reaction.

Step 5: Synthesis of compound WX128-6 Raw material WX128-5 (210.00 mg, 647.80 μmol), raw material WX034-1 (320.20 mg, 680.19 μmol) and solvent 1,4-dioxane (2 mL) in a pre-dried reaction bottle. , Water (0.6 mL), followed by potassium acetate (127.15 mg, 1.30 mmol), replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (47.40 mg, 64.78 μmol) was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 80 ° C. for 12 hours. After completion of the reaction, the mixture was directly rotated and dried, purified by flash column chromatography separation (petroleum ether: ethyl acetate = 1: 0 to 0: 1, and methylene chloride: methanol = 100: 1), and the target compound was WX128-6. Got

Step 6: Synthesis of compounds WX128, WX129
WX128-6 is SFC (Instrument: Thar SFC80 preparative SFC; Chromatography column: Chiralpak AS-H 250 * 30mm id 5μ; Mobile phase: A: CO2, B: MeOH (0.1% NH ₃ H ₂ O); Gradient: B % = 42%; Flow velocity: 70 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by a pair of enantiomers WX128 (holding time: 3.143 min) and WX129 (holding time: 100 bar) 3.134 min) was obtained. WX128: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.32 (d, J = 2.2 Hz, 1H), 8.15 --8.08 (m, 3H), 8.01 (d, J = 2.2 Hz, 1H), 7.87 --7.82 (m, 1H), 7.80 --7.76 (m, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.14 --7.09 (m, 1H), 5.60 (br d, J = 4.8 Hz, 1H) , 5.37 (quin, J = 6.1 Hz, 1H), 4.22 --4.14 (m, 1H), 4.09 --4.01 (m, 1H), 3.03 --2.90 (m, 1H), 2.75 (d, J = 4.8 Hz, 3H) ), 1.34 (d, J = 6.1 Hz, 6H), 1.29 (d, J = 7.0 Hz, 3H). WX129: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.31 (d, J = 1.8 Hz, 1H), 8.14 --8.08 (m, 3H), 8.01 (d, J = 2.2 Hz, 1H), 7.87 --7.82 (m, 1H), 7.80 --7.75 (m, 1H), 7.58 (s, 1H), 7.28 (s, 1H), 7.14 --7.09 (m, 1H), 5.61 (br d, J = 4.4 Hz, 1H) , 5.37 (td, J = 6.1, 12.3 Hz, 1H), 4.22 --4.14 (m, 1H), 4.09 --4.00 (m, 1H), 3.02 --2.89 (m, 1H), 2.75 (d, J = 4.8 Hz) , 3H), 1.34 (d, J = 6.1 Hz, 6H), 1.29 (d, J = 7.0 Hz, 3H).

Example 71: WX130, WX131

Step 1: Synthesis of compound WX130-3.
Compound WX130-1 (1 g, 4.93 mmol) and pyridine (6 mL) were added in that order to a pre-dried reaction bottle, and finally compound WX130-2 (1.04 g, 4.93 mmol) was added. The reaction was then replaced with nitrogen gas, and the reaction was completed after stirring at 25 ° C. for 5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and the mixture was purified by flash column chromatography separation (petroleum ether: mobile phase ethyl acetate = 10: 1 to 5: 1) to obtain the target compound WX130-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.94 --7.77 (m, 2H), 7.79 --7.71 (m, 2H), 7.50 --7.43 (m, 2H), 6.92 (s, 1H), 3.83 (s, 3H).

Step 2: Synthesis of compound WX130-4.
Compound WX130-3 (0.15 g, 397.20 μmol), bis (pinacolato) diboron (110.95 mg, 436.92 μmol), potassium acetate (77.96 mg, 794.41 μmol) and 1,4-dioxane (3 mL) in a dry reaction bottle. Was added, replaced with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (29.06 mg, 39.72 μmol) was added. After that, it was replaced with nitrogen gas, heated to 110 ° C. and stirred for 3 hours, and then the reaction was completed. After lowering the temperature of the reaction solution, it was distilled under reduced pressure to remove the solvent to obtain compound WX130-4, which was used as it was in the next step. Step 3: Synthesis of compound WX130-5.
Compound WX130-4 (0.2 g, 470.91 μmol), compound WX034-1 (0.15 g, 462.72 μmol), 1,4-dioxane (2 mL), water (0.2 mL) and potassium acetate (0.2 g) in a pre-dried reaction bottle. 136.23 mg, 1.39 mmol) were added in sequence, followed by replacement with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (33.86 mg, 46.27 μmol) was added. .. The reaction was completed after further replacement with nitrogen gas, heating to 110 ° C. and stirring for 3 hours. The reaction mixture was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain the target compound WX130-5. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.09 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 2.2, 8.6 Hz, 1H), 7.78 (d, J = 8.6 Hz, 3H), 7.56 --7.51 (m, 2H), 4.25 (dd, J = 4.9, 13.5) Hz, 1H), 4.03 (dd, J = 9.9, 13.5 Hz, 1H), 3.77 (s, 3H), 3.07 --2.96 (m, 1H), 2.62 (s, 3H), 1.25 (s, 3H).

Step 4: Synthesis of compounds WX130 and WX131.
Compound WX130-5 (0.12 g, 221.40 μmol) is SFC (separation condition: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O, MeOH]; B%: 50% Separation by -50%, 15 min) gave a pair of enantiomers WX130 (Rt = 3.267min) and WX131 (Rt = 3.750min). WX130: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.38 (d, J = 1.8 Hz, 1H), 8.22 --8.17 (m, 2H), 8.04 (td, J = 2.6, 5.8 Hz, 2H), 7.82 --7.76 (m, 3H), 7.53 (d, J = 8.3 Hz, 2H), 4.25 (dd, J = 4.8, 13.2 Hz, 1H), 4.03 (dd, J = 9.9, 13.4 Hz, 1H), 3.79 ( s, 3H), 3.02 (br d, J = 10.1 Hz, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). WX131: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.36 (d, J = 2.2 Hz, 1H), 8.20 --8.15 (m, 2H), 8.05 --8.00 (m, 2H), 7.82 --7.74 (m, 3H), 7.52 (d, J = 8.3 Hz, 2H) ), 4.24 (dd, J = 4.8, 13.6 Hz, 1H), 4.03 (dd, J = 9.9, 13.4 Hz, 1H), 3.79 (s, 3H), 3.07 --2.94 (m, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 72: WX132, WX133

Step 1: Synthesis of compound WX132-3 Compound WX132-1 (1 g, 4.93 mmol) and pyridine (6 mL) were added to a pre-dried reaction bottle, and finally compound WX132-2 (1.05 g, 4.93 mmol, 659.20 μL) was added. After that, it was replaced with nitrogen gas, and the reaction was completed after stirring at 25 ° C. for 5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and the mixture was purified by column chromatography separation (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain compound WX132-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.94 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.68 (ddd, J = 2.3, 7.1, 9.3 Hz, 1H) ), 7.63 --7.57 (m, 1H), 7.33 --7.27 (m, 1H), 6.90 (s, 1H), 3.93 --3.79 (m, 3H).

Step 2: Synthesis of compound WX132-4.
Compound WX132-3 (0.15 g, 395.59 μmol), bis (pinacolato) diboron (110.50 mg, 435.15 μmol), potassium acetate (77.65 mg, 791.19 μmol) and 1,4-dioxane (3 mL) in a dry reaction bottle. Was added, replaced with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (28.95 mg, 39.56 μmol) was added. After that, it was replaced with nitrogen gas, heated to 110 ° C. and stirred for 3 hours, and then the reaction was completed. After lowering the temperature of the reaction solution, it was distilled under reduced pressure to remove the solvent to obtain the target compound WX132-4, which was used as it was in the next step.

Step 3: Synthesis of compound WX132-5.
Compound WX132-4 (0.2 g, 470.91 μmol), compound WX034-1 (0.15 g, 462.72 μmol), 1,4-dioxane (2 mL), water (0.2 mL) and potassium acetate (0.2 mL) in a pre-dried reaction bottle. 136.23 mg, 1.39 mmol) were added in sequence, followed by replacement with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (33.86 mg, 46.27 μmol) was added. .. The reaction was completed after further replacement with nitrogen gas, heating to 110 ° C. and stirring for 3 hours. The reaction mixture was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain compound WX132-5. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.41 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J = 2.2 Hz, 1H), 8.07 (dd, J = 2.2, 8.4 Hz, 1H), 7.83 --7.74 (m, 2H), 7.66 --7.60 (m, 1H), 7.48 --7.38 (m, 1H), 4.24 (dd) , J = 5.0, 13.3 Hz, 1H), 4.03 (dd, J = 9.8, 13.3 Hz, 1H), 3.80 (s, 3H), 3.05 --2.97 (m, 1H), 2.64 --2.61 (m, 3H), 1.25 (s, 3H).

Step 4: Synthesis of compounds WX132, WX133.
Compound WX132-5 was added by SFC (separation conditions: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O, MeOH]; B%: 50% -50%, 15 min). Separation gave a pair of enantiomers WX132 (Rt = 2.859min) and WX133 (Rt = 3.124min). WX132: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.39 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.10 --8.04 ( m, 2H), 7.83 --7.74 (m, 2H), 7.63 (br d, J = 8.8 Hz, 1H), 7.48 --7.38 (m, 1H), 4.24 (dd, J = 4.8, 13.2 Hz, 1H), 4.03 (dd, J = 10.1, 13.6 Hz, 1H), 3.80 (s, 3H), 3.06 --2.96 (m, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). WX133: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.39 (d, J = 1.8 Hz, 1H), 8.27 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.10 --8.04 ( m, 2H), 7.83 --7.74 (m, 2H), 7.63 (br d, J = 8.8 Hz, 1H), 7.48 --7.38 (m, 1H), 4.24 (dd, J = 4.8, 13.2 Hz, 1H), 4.03 (dd, J = 10.1, 13.6 Hz, 1H), 3.80 (s, 3H), 3.06 --2.96 (m, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 73: WX134, WX135

Step 1: Synthesis of compound WX134-3 Compound WX134-1 (1 g, 4.93 mmol) and pyridine (6 mL) are added in order to a pre-dried reaction bottle, and finally compound WX134-2 (1.03 g, 4.93 mmol). , 659.20 μL) was added. The reaction was then replaced with nitrogen gas, and the reaction was completed after stirring at 25 ° C. for 5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and the mixture was purified by flash column chromatography separation (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain the target compound WX134-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.86 (d, J = 2.2 Hz, 1H), 7.82 (d, J = 2.1 Hz, 1H), 7.76 (t, J = 7.8 Hz, 1H), 7.22 ( s, 1H), 7.05 (d, J = 8.1 Hz, 1H), 6.99 (d, J = 11.1 Hz, 1H), 3.90 (s, 3H), 2.40 (s, 3H).

Step 2: Synthesis of compound WX134-4 Compound WX134-3 (0.15 g, 399.77 μmol), bis (pinacolato) diboron (101.52 mg, 399.77 μmol), potassium acetate (78.47 mg, 799.55 μmol) in a pre-dried reaction bottle. And 1,4-dioxane (3 mL) were added in sequence, replaced with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (29.25 mg, 39.98 μmol) was added. Added. After that, it was replaced with nitrogen gas, heated to 110 ° C. and stirred for 3 hours, and then the reaction was completed. After lowering the temperature of the reaction solution, it was distilled under reduced pressure to remove the solvent to obtain the target compound WX134-4, which was used as it was in the next step.

Step 3: Synthesis of Compound WX134-5 Compound WX134-4 (0.2 g, 473.62 μmol), Compound WX034-1 (0.13 g, 401.02 μmol), 1,4-dioxane (2 mL), in a pre-dried reaction bottle. Water (0.2 mL) and potassium acetate (118.07 mg, 1.20 mmol) were added in sequence, followed by replacement with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride ( 29.34 mg, 40.10 μmol) was added. The reaction was completed after further replacement with nitrogen gas, heating to 110 ° C. and stirring for 3 hours. The reaction mixture was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain compound WX134-5. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.35 (d, J = 2.0 Hz, 1H), 8.22 (d, J = 2.4 Hz, 1H), 8.18 (s, 1H), 8.05 --8.00 (m, 2H), 7.77 (d, J = 8.4 Hz, 1H), 7.70 (t, J = 7.8 Hz, 1H), 7.16 --7.08 (m, 2H), 4.24 (dd, J = 4.9, 13.5 Hz, 1H), 4.03 (dd, J = 10.0, 13.3 Hz, 1H), 3.85 (s, 3H), 3.05 --2.95 (m, 1H), 2.64 --2.61 (m, 3H), 2.39 (s, 3H), 1.25 (s, 3H).

Step 4: Synthesis of Compounds WX134 and WX135 Compound WX134-5 (0.12 g, 222.40 μmol) is SFC (chromatographic column: Chiralpak AS-H 250 * 30 mm id 5 μ; mobile phase: A: CO ₂ , B: MeOH (0.1). % NH ₃ H ₂ O); Gradient: B% = 50%; Flow velocity: 80 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by a pair of enantiomer WX134 ( Rt = 2.996min) and WX135 (Rt = 3.335min) were obtained. WX134: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.32 (d, J = 2.2 Hz, 1H), 8.21 --8.16 (m, 2H), 8.02 --7.98 (m, 2H), 7.76 --7.67 (m) , 2H), 7.16 --7.07 (m, 2H), 4.24 (dd, J = 4.8, 13.6 Hz, 1H), 4.02 (dd, J = 9.9, 13.4 Hz, 1H), 3.84 (s, 3H), 3.06- 2.96 (m, 1H), 2.64 --2.60 (m, 3H), 2.39 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). WX135: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.32 (d, J = 1.8 Hz, 1H), 8.19 --8.17 (m, 2H), 8.00 --7.97 (m, 2H), 7.75 --7.68 (m) , 2H), 7.15 --7.30 (m, 2H), 4.24 (dd, J = 4.8, 13.6 Hz, 1H), 4.02 (dd, J = 9.9, 13.4 Hz, 1H), 3.84 (s, 3H), 3.00 ( ddd, J = 4.8, 7.0, 9.6 Hz, 1H), 2.63 --- 2.60 (m, 3H), 2.39 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 74: WX136, WX137

Step 1: Synthesis of compound WX136-2 Compound WX087-3 (0.2 g, 544.36 μmol) and pyridine (6 mL) are added in order to a pre-dried reaction bottle, and finally compound WX136-1 (133.65 mg, 544.36 μmol). ) Was added. After that, it was replaced with nitrogen gas, and the reaction was completed after stirring at 80 ° C. for 5 hours. Purification by preparative TLC (methylene chloride: methanol = 10: 1) gave the target compound WX136-2. ¹ H NMR (400MHz, METHANOL-d4) δ = 8.42 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.10 (d, J = 2.6) Hz, 1H), 8.07 (dd, J = 2.2, 8.8 Hz, 1H), 7.97 (d, J = 1.3 Hz, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.71 --7.74 (m, 2H) ), 4.25 (dd, J = 4.8, 13.6 Hz, 1H), 4.03 (dd, J = 9.6, 13.6 Hz, 1H), 3.78 (s, 3H), 3.04 --2.95 (m, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Step 2: Synthesis of compounds WX136 and WX137 Compound WX136-2 (0.12 g, 208.17 μmol) is SFC (separation condition column: Chiralpak AS-H 250 * 30mm id 5 μm; mobile phase: A: CO2, B: MeOH (0.1%) NH ₃ H ₂ O); Gradient: B% = 50%; Flow velocity: 80 g / min; Wavelength: 220 nm; Column temperature: 40 ° C; Back pressure: 100 bar) Separated by a pair of enantiomer WX136 (Rt) = 3.337 min) and WX137 (Rt = 3.726 min) were obtained. WX136: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.41 (d, J = 1.8 Hz, 1H), 8.29 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.11 --8.04 ( m, 2H), 7.97 (s, 1H), 7.78 (d, J = 8.3 Hz, 1H), 7.71 --7.64 (m, 2H), 4.24 (dd, J = 4.8, 13.6 Hz, 1H), 4.03 (dd) , J = 9.9, 13.4 Hz, 1H), 3.77 (s, 3H), 2.99 (br d, J = 9.6 Hz, 1H), 2.62 (s, 3H), 1.24 (d, J = 6.6 Hz, 3H). WX137: 1H NMR (400MHz, METHANOL-d ₄ ) δ = 8.42 (d, J = 1.8 Hz, 1H), 8.30 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.11 --8.05 (m) , 2H), 7.97 (d, J = 1.3 Hz, 1H), 7.78 (d, J = 8.8 Hz, 1H), 7.70 --7.64 (m, 2H), 4.24 (dd, J = 4.8, 13.2 Hz, 1H) , 4.03 (dd, J = 9.9, 13.4 Hz, 1H), 3.78 (s, 3H), 3.05 --2.96 (m, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 75: WX138, WX139

Step 1: Synthesis of compound WX138-2 WX087-3 (150 mg, 408.27 μmol) and WX138-1 (551.39 mg, 2.45 mmol, 5.94 μL) were added to a pre-dried 40 mL reaction bottle, followed by pyridine (6). mL) was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, preparative HPLC (method: chromatography column: Luna C18 100 * 30 5 μ; mobile phase: Separation with [water (0.1% TFA) -ACN]; B%: 25% -55%, 10 min) gave the target compound WX138-2.

Step 2: Synthesis of compounds WX138 and WX139
WX138-2 is purified by SFC separation (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 6 min) to obtain the target compound WX138 ( Rt = 3.240 min) and WX139 (Rt = 3.611 min) were obtained. WX138: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.32 (d, J = 2.0 Hz, 1H), 8.23 (s, 1H), 8.19 (d, J = 2.2 Hz, 1H), 8.00 (dd, J = 2.2, 8.6 Hz, 1H), 7.98 (d, J = 2.2 Hz, 1H), 7.85 (dd, J = 1.0, 8.0 Hz, 1H), 7.75 (d, J = 8.4 Hz, 1H), 7.61 (dd) , J = 1.0, 8.0 Hz, 1H), 7.28 (t, J = 7.9 Hz, 1H), 4.24 (dd, J = 4.9, 13.5 Hz, 1H), 4.03 (dd, J = 9.9, 13.5 Hz, 1H) , 3.83 (s, 3H), 3.06 --2.95 (m, 1H), 2.77 (s, 3H), 2.61 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H). WX139: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.31 (d, J = 2.0 Hz, 1H), 8.22 --8.17 (m, 2H), 8.01 --7.96 (m, 2H), 7.85 (dd, J = 1.0, 8.0 Hz, 1H), 7.75 (d, J = 8.6 Hz, 1H), 7.61 (dd, J = 0.9, 8.2 Hz, 1H), 7.28 (t, J = 8.3 Hz, 1H), 4.23 (dd, dd, J = 4.9, 13.5 Hz, 1H), 4.02 (dd, J = 9.8, 13.3 Hz, 1H), 3.82 (s, 3H), 3.04 --2.94 (m, 1H), 2.77 (s, 3H), 2.61 (s) , 3H), 1.23 (d, J = 7.1 Hz, 3H).

Example 76: WX140, WX141

Step 1: Synthesis of compound WX140-2 WX087-3 (150 mg, 408.27 μmol) and WX140-1 (233.51 mg, 1.22 mmol, 178.25 μL) were added to a pre-dried 40 mL reaction bottle, followed by pyridine (5). mL) was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, preparative HPLC (method: chromatography column: Phenomenex Synergi C18 100 * 30 mm * 4 μm; transfer Separation by phase: [water (0.1% TFA) -MeOH]; B%: 20% -45%, 10 min) gave the desired compound WX140-2.

Step 2: Synthesis of compounds WX140 and WX141
WX140-2 is purified by SFC separation (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 8.5 min) and paired with enantiomers. WX140 (Rt = 3.144 min) and WX141 (Rt = 3.504 min) were obtained. WX140: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.37 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.05 --8.01 (m) , 2H), 7.77 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 7.1 Hz, 1H), 7.46 --7.33 (m, 2H), 4.24 (dd, J = 4.9, 13.5 Hz, 1H), 4.02 (dd, J = 9.9, 13.5 Hz, 1H), 3.79 (s, 3H), 3.05 --2.94 (m, 1H), 2.61 (s, 3H), 2.37 (s, 3H) ), 1.24 --1.21 (m, 1H), 1.23 (d, J = 6.8 Hz, 2H). WX141: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.37 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.06 --8.01 (m) , 2H), 7.76 (d, J = 8.6 Hz, 1H), 7.65 (s, 1H), 7.60 (d, J = 7.3 Hz, 1H), 7.46 --7.33 (m, 2H), 4.24 (dd, J = 4.9, 13.5 Hz, 1H), 4.02 (dd, J = 9.9, 13.5 Hz, 1H), 3.78 (s, 3H), 3.04 --2.95 (m, 1H), 2.61 (s, 3H), 2.37 (s, 3H) ), 1.23 (d, J = 7.1 Hz, 3H).

Example 77: WX142, WX143

Step 1: Synthesis of compound WX142-1.

WX087-3 (748.14 mg, 3.27 mmol), 2-fluoro-4-chlorobenzenesulfonyl chloride (200 mg, 544.36 μmol) and solvent pyridine (10 mL) were added to a pre-dried reaction bottle and further at 25 ° C. 12 Stirred for hours. After completion of the reaction, water (5 mL) was added to the reaction solution, extracted with methylene chloride (10 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotary-dried under reduced pressure to obtain a crude product. , Separation by preparative HPLC and purification to obtain the target compound WX142-1.

Step 2: Synthesis of compounds WX142, WX143.

WX142-1 was separated by SFC (chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 6 min) and paired with enantiomer WX142 (retention time:: 2.750 min) and WX143 (holding time: 2.765 min) were obtained. WX142: 1H NMR (400MHz, METHANOL-d4) δ = 8.38 (s, 1H), 8.27 (s, 1H), 8.21 (s, 1H), 8.07 --8.01 (m, 2H), 7.82 --7.74 (m, 2H) ), 7.46 (d, J = 9.9 Hz, 1H), 7.34 (d, J = 8.4 Hz, 1H), 4.24 (dd, J = 4.7, 13.4 Hz, 1H), 4.03 (dd, J = 10.0, 13.4 Hz) , 1H), 3.82 (s, 3H), 3.31 (s, 25H), 3.04 --2.93 (m, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H) WX143: 1H NMR ( 400MHz, METHANOL-d ₄ ) δ = 8.39 (s, 1H), 8.28 (s, 1H), 8.22 (s, 1H), 8.09 --8.01 (m, 2H), 7.83 --7.74 (m, 2H), 7.47 ( d, J = 9.7 Hz, 1H), 7.34 (d, J = 8.3 Hz, 1H), 4.24 (dd, J = 5.0, 13.3 Hz, 1H), 4.10 --3.98 (m, 1H), 3.82 (s, 3H) ), 3.15 --2.95 (m, 1H), 2.62 (s, 3H), 1.31 --1.20 (m, 4H).

Example 78: WX144, WX145

Step 1: Synthesis of compound WX144-2 Raw material WX144-1 (1 g, 4.93 mmol), raw material 3,5-dimethylbenzenesulfonyl chloride (1.51 g, 7.39 mmol) and solvent pyridine (10 mL) in a pre-dried reaction bottle. ) Was added, and the mixture was further stirred at 25 ° C. for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, extracted with methylene chloride (10 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then rotary-dried under reduced pressure for flash column chromatography. The compound was separated by chromatography (petroleum ether: ethyl acetate = 1: 0 to 10: 1) and purified to obtain the target compound WX144-2. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 7.90 (d, J = 2.2 Hz, 1H), 7.83 (d, J = 2.4 Hz, 1H), 7.39 (s, 2H), 7.24 (s, 1H), 7.25 --7.23 (m, 1H), 3.74 (s, 4H), 2.33 (s, 8H).

Step 2: Synthesis of compound WX144-3 WX144-2 (280 mg, 754.21 μmol), bis (pinacolato) diboron (191.52 mg, 754.21 μmol) and solvent 1,4-dioxane (3 mL) in a pre-dried reaction bottle. Was added, followed by potassium acetate (148.04 mg, 1.51 mmol), replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (55.19 mg, 75.42 μmol). ) Was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 90 ° C. for 12 hours. After completion of the reaction, the target compound WX144-3 was obtained and directly put into the next reaction.

Step 3: Synthesis of compound WX144-4 Raw material WX144-3 (210.00 mg, 647.80 μmol), raw material WX034-1 (298.08 mg, 712.58 μmol) and solvent water (0.5 mL), 1,4 in a pre-dried reaction bottle. -Dioxane (2 mL) was added, followed by potassium acetate (127.15 mg, 1.30 mmol), replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride. (47.40 mg, 64.78 μmol) was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 80 ° C. for 12 hours. After completion of the reaction, water (2 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then preparative thin layer chromatography (methylene chloride:). It was separated and purified by methanol = 15: 1), and further purified by preparative HPLC to obtain the target compound WX144-4.

Step 4: Synthesis of compounds WX144, WX145
WX144-4 was separated by SFC (chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 7 min) and paired with enantiomer WX144 (retention time:: 2.725 min) and WX145 (holding time: 2.727 min) were obtained. WX144: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.35 (d, J = 1.8 Hz, 1H), 8.14 --8.10 (m, 2H), 8.03 (d, J = 2.2 Hz, 1H), 7.88 --7.83 (m, 1H), 7.80 --7.76 (m, 1H), 7.46 (s, 2H), 7.18 (s, 1H), 7.04 (s, 1H), 5.75 (br s, 1H), 4.22 --4.13 (m, 1H) 1H), 4.10 --4.00 (m, 1H), 3.91 (s, 3H), 3.02 --2.91 (m, 1H), 2.74 (d, J = 4.9 Hz, 3H), 2.34 (s, 6H), 1.73 (br s, 6H), 1.29 (d, J = 6.8 Hz, 3H). WX145: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.35 (d, J = 1.8 Hz, 1H), 8.12 (s, 2H), 8.03 (d, J = 2.2 Hz, 1H), 7.90 --7.83 (m) , 1H), 7.82 --7.72 (m, 1H), 7.46 (s, 2H), 7.18 (s, 1H), 7.05 (s, 1H), 5.77 (br d, J = 4.6 Hz, 1H), 4.23 --4.11 (m, 1H), 4.09 --3.97 (m, 1H), 3.91 (s, 3H), 3.03 --2.89 (m, 1H), 2.74 (d, J = 4.9 Hz, 3H), 2.34 (s, 6H), 1.82 --1.66 (m, 6H), 1.29 (d, J = 6.8 Hz, 3H).

Example 79: WX146, WX147

Step 1: Synthesis of compound WX146-2 WX087-3 (150 mg, 408.27 μmol) and WX146-1 (517.03 mg, 2.45 mmol, 333.57 μL) were added to a pre-dried reaction bottle, followed by pyridine (1 mL). ) Was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, preparative HPLC (method: chromatography column: Agela Durashell C18 150 * 25mm 5 μm; mobile phase : [Water (10 mM NH4HCO3) -ACN]; B%: 33% -63%, 10 min) separated to give the target compound WX146-2.

Step 2: Synthesis of compounds WX146 and WX147
WX146-2 is separated by SFC (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 8 min) and paired with enantiomer WX146 ( Rt = 1.289 min) and WX147 (Rt = 1.601 min) were obtained. WX146: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.31 (d, J = 2.2 Hz, 1H), 8.21 --8.15 (m, 2H), 8.05 (dd, J = 1.3, 7.9 Hz, 1H), 8.01 --7.96 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.65 --7.53 (m, 2H), 7.49 --7.42 (m, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H ), 4.02 (dd, J = 9.9, 13.5 Hz, 1H), 3.85 (s, 3H), 3.05 --2.91 (m, 1H), 2.61 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H) .. WX147: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.30 (d, J = 2.0 Hz, 1H), 8.20 --8.15 (m, 2H), 8.05 (dd, J = 1.3, 7.9 Hz, 1H), 8.01 --7.95 (m, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.62 --7.52 (m, 2H), 7.46 (ddd, J = 1.8, 7.1, 7.9 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 4.02 (dd, J = 9.9, 13.5 Hz, 1H), 3.05 --2.94 (m, 1H), 1.23 (d, J = 7.1 Hz, 3H).

Example 80: WX148, WX149

Step 1: Synthesis of compound WX148-2 WX087-3 (200 mg, 544.36 μmol) and WX148-1 (266.32 mg, 1.09 mmol, 5.56 μL) are added to a pre-dried reaction bottle, followed by pyridine (5 mL). ) Was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, preparative HPLC (method: chromatography column: Agela Durashell C18 150 * 25mm 5 μm; mobile phase : [Water (10 mM NH4HCO3) -ACN]; B%: 33% -63%, 10 min) separated to give the target compound WX148-2.

Step 2: Synthesis of compounds WX148 and WX149
WX148-2 is separated and purified by SFC (purification method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 7 min) to form a pair of enantiomers. WX148 (Rt = 0.995 min) and WX149 (Rt = 1.162 min) were obtained. WX148: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 2.2 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.10 (d, J = 2.4 Hz, 1H), 8.05 (dd, J = 2.2, 8.6 Hz, 1H), 7.97 (d, J = 8.4 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.77 (d, J = 8.6 Hz, 1H), 4.24 (dd, J = 5.0, 13.3 Hz, 1H), 4.03 (dd, J = 9.8, 13.3 Hz, 1H), 3.70 (s, 3H), 3.07 --2.92 (m, 1H) ), 2.61 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H). WX149: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.41 (d, J = 2.0 Hz, 1H), 8.28 (d, J = 2.4 Hz, 1H), 8.19 (s, 1H), 8.11 (d, J = 2.4 Hz, 1H), 8.06 (dd, J = 2.2, 8.4 Hz, 1H), 7.97 (d, J = 8.2 Hz, 2H), 7.84 (d, J = 8.4 Hz, 2H), 7.78 (d, J = 8.6 Hz, 1H), 4.24 (dd, J = 4.9, 13.5 Hz, 1H), 4.03 (dd, J = 9.9, 13.5 Hz, 1H), 3.70 (s, 3H), 3.05 --2.94 (m, 1H) ), 1.23 (d, J = 7.1 Hz, 3H).

Example 81: WX150, WX151

Step 1: Synthesis of compound WX150-2 WX087-3 (150 mg, 408.27 μmol) and WX150-1 (601.41 mg, 2.45 mmol, 5.94 μL) are added to a pre-dried reaction bottle, followed by pyridine (5 mL). ) Was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform preparative HPLC (method: chromatography column: chromatography column: Agela Durashell C18 150 * 25 mm). Separation by 5 μm; mobile phase: [water (10 mM NH4HCO3) -ACN]; B%: 33% -63%) gave the target compound WX150-2.

Step 2: Synthesis of compounds WX150 and WX151
WX150-2 is separated and purified by SFC (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 10 min) to form a pair of enantiomers. WX150 (Rt = 1.406 min) and WX151 (Rt = 1.794 min) were obtained. WX150: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.31 (d, J = 2.0 Hz, 1H), 8.20 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.02 --7.95 ( m, 3H), 7.80 --7.71 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 4.02 (dd, J = 9.7, 13.5 Hz) , 1H), 3.82 (s, 3H), 3.05 --2.92 (m, 1H), 2.61 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H). WX151: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.27 (s, 1H), 8.23 (d, J = 2.2 Hz, 1H), 8.06 --7.94 ( m, 3H), 7.83 --7.72 (m, 2H), 7.42 (t, J = 8.0 Hz, 1H), 4.24 (dd, J = 4.9, 13.5 Hz, 1H), 4.11 --3.95 (m, 1H), 3.82 (s, 3H), 3.06 --2.93 (m, 1H), 2.61 (s, 3H), 1.23 (d, J = 7.1 Hz, 3H).

Example 82: WX152, WX153

Step 1: Synthesis of compound WX152-2
WX087-3 (0.15 g, 269.58 μmol) and WX152-1 (0.1 g, 407.31 μmol) were added to pyridine (1 mL) and reacted at 25 ° C. for 16 hours. After completion of the reaction, the reaction mixture was rotationally dried, diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was rotationally dried, and further by preparative TLC (petroleum ether: ethyl acetate = 0: 1). Purification was performed to obtain the target compound WX152-2.

Step 2: Synthesis of compounds WX152 and WX153
WX152-2 is separated by SFC (chromatography column: OJ (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 30% -30%) and enantiomer WX152 (rt). = 3.450 min) and WX153 (rt = 3.827 min) were obtained. WX152: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.33 (br s, 1 H), 8.38 (s, 1 H), 8.26 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.08 (dd, J = 8.5, 2.5 Hz, 1 H), 7.86 --7.94 (m, 4 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.58 (dd, J = 8.5, 2.0 Hz, 1 H), 4.04 --4.12 (m, 1 H), 3.92 --4.02 (m, 1 H), 3.69 (s, 3 H), 2.87 (br dd, J = 14.8, 6.8 Hz, 1 H) , 2.49 (br s, 3 H), 1.09 (d, J = 7.0 Hz, 3 H). WX153: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.33 (br s, 1 H), 8.37 (s, 1 H), 8.26 (d, J = 2.0 Hz, 1 H), 8.19 (s, 1 H), 8.07 (dd, J = 8.5, 2.5 Hz, 1 H), 7.86 --7.95 (m, 4 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.58 (dd, J = 8.5, 2.0 Hz, 1 H), 4.04 --4.13 (m, 1 H), 3.90 --4.02 (m, 1 H), 3.69 (s, 3 H), 2.87 (br dd, J = 15.1, 6.5 Hz, 1 H) , 2.49 (br s, 3 H), 1.09 (d, J = 7.0 Hz, 3 H).

Example 83: WX154, WX155

Step 1: Synthesis of compound WX154-2
WX087-3 (0.15 g, 269.58 μmol) and WX154-1 (0.084 g, 402.61 μmol) were added to pyridine (1 mL), and 16 reactions were carried out at 25 ° C. After completion of the reaction, the reaction mixture was rotationally dried, diluted with water (50 mL), extracted with DCM (50 mL), the organic phase was rotationally dried, and further by preparative TLC (petroleum ether: ethyl acetate = 0: 1). Purification was performed to obtain the target compound WX154-2.

Step 2: Synthesis of compounds WX154 and WX155
WX154-2 is separated by SFC (chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 55% -55%) and enantiomer WX154 (rt). = 2.854 min) and WX155 (rt = 2.999 min) were obtained. WX154: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.11 (br s, 1 H), 8.40 (d, J = 2.0 Hz, 1 H), 8.21 --8.33 (m, 2 H), 8.12 ( dd, J = 8.5, 2.0 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 2 H), 7.77 --7.76 (m, 2 H), 7.65 --7.73 (m, 1 H), 7.40 (t, J = 9.0 Hz, 1 H), 3.97 --4.21 (m, 2 H), 3.77 (s, 3 H), 2.92 (br dd, J = 14.8, 6.8 Hz, 1 H), 2.54 (br s, 3 H) ), 2.34 (s, 3 H), 1.14 (d, J = 6.5 Hz, 3 H). WX155: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 10.12 (br s, 1 H), 8.41 (d, J = 2.0 Hz, 1 H), 8.29 (d, J = 2.0 Hz, 1 H) , 8.24 (s, 1 H), 8.12 (dd, J = 8.5, 2.0 Hz, 1 H), 7.95 (d, J = 2.0 Hz, 2 H), 7.77 --7.84 (m, 2 H), 7.65 --7.73 (m, 1 H), 7.39 (t, J = 9.0 Hz, 1 H), 3.95 ―― 4.19 (m, 2 H), 3.76 (s, 3 H), 2.83 ―― 2.98 (m, 1 H), 2.53 ( br s, 3 H), 2.33 (s, 3 H), 1.13 (d, J = 6.5 Hz, 3 H).

Example 84: WX156, WX157

Step 1: Synthesis of compound WX156-2
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (3.0 mL), WX156-1 (116.56 mg, 530.75 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 30 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX156-2 was obtained. MS-ESI m / z: 573.1 [M + Na] ⁺ , 575.1 [M + Na + 2] ⁺ .

Step 2: Synthesis of compounds WX156 and WX157
WX156-2 is separated and purified by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; B%: 45% -45%), and paired. WX156 (Rt = 1.632 min) and WX157 (Rt = 1.892 min) were obtained. WX156: ^{1 1} H NMR (400MHz, CDCl ₃ ) δ: 8.31 (s, 1H), 8.16 (d, J = 2.0 Hz, 1H), 8.11-8.02 (m, 2H), 7.98 (br d, J = 2.3 Hz) , 2H), 7.88 --7.80 (m, 1H), 7.79 --7.68 (m, 1H), 7.28 (t, J = 8.5 Hz, 1H), 5.54 (br s, 1H), 4.23 --4.04 (m, 1H) , 4.04 --3.90 (m, 1H), 3.85 (s, 3H), 2.89 (br s, 1H), 2.67 (d, J = 4.8 Hz, 3H). WX157: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.31 8.36 --8.29 (m, 1H), 8.37 --8.15 (m, 1H), 8.21 --8.14 (m, 1H), 8.10 --8.07 (m, 1H), 8.06 (s, 1H), 8.02 --7.92 (m, 2H), 7.90 --7.80 (m, 1H), 7.80 --7.68 (m, 1H), 7.28 (t, J = 8.5 Hz, 1H), 6.95 (s, 1H), 5.54 (br s, 1H), 4.03 --3.92 (m, 1H), 3.85 (s, 3H), 2.96 --2.83 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H).

Example 85: WX158, WX159

Step 1: Synthesis of compound WX158-1
WX158-1 (2 g, 8.42 mmol) and sodium ethoxide (5 g, 73.48 mmol) were added to ethanol (100 mL) and reacted at 75 ° C. for 16 hours. After completion of the reaction, the reaction solution was spin-dried, water (100 mL) was added to dilute it, extraction was performed with EA (50 mL × 3), and the organic phase was spin-dried to obtain the target compound WX158-2.
Step 2: Synthesis of compound WX158-3
Dissolve WX158-2 in methanol (100 mL) and methylene chloride (10 mL), add zinc powder (1.90 g, 29.03 mmol) and ammonium chloride (1.43 g, 26.73 mmol) at 25 ° C, and further at 75 ° C. Stirred for 4 hours. After completion of the reaction, the reaction mixture was filtered, the filtrate was spin-dried, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was spin-dried, and the target compound WX158- 3 was obtained and used as it was for the next reaction. MS-ESI m / z: 216.9 [M + H] ⁺ , 218.9 [M + H + 2] ⁺ .

Step 3: Synthesis of compound WX158-4
WX158-3 (1 g, 4.61 mmol), bis (pinacolato) diboron (1.20 g, 4.73 mmol), Pd (dppf) Cl _{2 (} 400.00 mg, 546.67 μmol), KOAc (1.40 g, 14.27 mmol) with nitrogen (50) It was added to mL), replaced with nitrogen gas three times, and reacted at 105 ° C. for 16 hours under the protection of nitrogen gas. After completion of the reaction, the reaction mixture was spin-dried, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was spin-dried, and column chromatography (PE: EA = 0% -10). %) Was separated and purified to obtain the target compound WX158-4. MS-ESI m / z: 265.1 [M + H] ⁺ .

Step 4: Synthesis of compound WX158-6
WX158-4 (1.2 g, 4.54 mmol) was dissolved in pyridine (50 mL), WX158-5 (1.10 g, 4.80 mmol, 0.7 mL) was added dropwise and stirred at 30 ° C. for 16 hours. After completion of the reaction, the reaction solution was spin-dried, diluted with water (50 mL), extracted with methylene chloride (50 × 3 mL), and the organic phase was spin-dried to give the target compound WX158-6. MS-ESI m / z: 375.0 [M + H] ⁺ .

Step 5: Synthesis of compound WX158-7
WX034-1 (0.17 g, 396.61 μmol), WX158-6 (0.23 g, 503.69 μmol), Pd (dppf) Cl2 (0.03 g, 41.00 μmol, 1.03e-1 eq), KOAc (0.12 g, 1.22 mmol) It was dissolved in dioxane (10 mL) and water (2 mL), replaced with nitrogen gas three times, and further reacted at 105 ° C. for 2 hours. After completion of the reaction, the reaction mixture was spin-dried, diluted with water (50 mL), extracted with ethyl acetate (50 mL × 3), the organic phase was spin-dried, and further column chromatography (petroleum ether: ethyl acetate = 0). %-50%) was separated and purified to obtain the target compound WX158-7.

Step 6: Synthesis of compounds WX158 and WX159
WX158-7 is separated by SFC (chromatography column: Chiralpak AS-H 250 * 30mm 5 μm; mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 35% -35%) and enantiomer WX158 (rt). = 3.525 min) and WX159 (rt = 3.996 min) were obtained. WX158: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.21 (br d, J = 7.03 Hz, 3 H) 1.33 (t, J = 7.03 Hz, 3 H) 2.67 (d, J = 4.77 Hz, 3 H) 2.84 --2.94 (m, 1 H) 3.89 --4.02 (m, 1 H) 4.04 --4.16 (m, 1 H) 4.25 --4.43 (m, 2 H) 5.68 (br s, 1 H) 6.91 --7.11 ( m, 1 H) 7.11 --7.25 (m, 2 H) 7.60 --7.83 (m, 2 H) 7.91 (s, 1 H) 7.98 --8.09 (m, 3 H) 8.20 (s, 1 H), MS-ESI m / z: 574.1 [M + H] ⁺ . WX159: ^{1 1} H NMR (400 MHz, CHLOROFORM-d) δ ppm 1.15 --1.22 (m, 3 H) 1.33 (t, J = 7.15 Hz, 3 H) 2.67 (d, J = 4.77 Hz, 3 H) 2.80- 2.98 (m, 1 H) 3.91 --4.03 (m, 1 H) 4.04 --4.16 (m, 1 H) 4.34 (q, J = 7.03 Hz, 2 H) 5.71 (br s, 1 H) 6.97 --7.08 (m) , 1 H) 7.13 --7.28 (m, 2 H) 7.62 --7.80 (m, 2 H) 7.91 (d, J = 1.76 Hz, 1 H) 7.97 --8.10 (m, 3 H) 8.20 (s, 1 H) , MS-ESI m / z: 574.1 [M + H] ⁺ .

Example 86: WX160, WX161

Step 1: Synthesis of compound WX160-2 Compound WX087-3 (0.15 g, 408.27 μmol) is dissolved in pyridine (3 mL), compound WX160-1 (110.28 mg, 489.93 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. According to TLC (ethyl acetate: methanol = 10: 1), it was shown that the raw materials had completely reacted, and the reaction solution was spin-dried. The compound was separated by a preparative silica gel plate (ethyl acetate: methanol = 10: 1) to obtain the target compound WX160-2.

Step 2: Synthesis of Compound WX160 and WX161 Compound WX160-2 is supercritical fluid chromatography (separation condition: chromatography column: Chiralpak AS-H 250 * 30mm 5 μm; mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B %: 45% -45%) to give enantiomers WX160 and WX161. WX160: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.29 (br s, 1 H), 8.22 --8.27 (m, 1 H), 8.17 (s, 1 H), 8.05 (dd, J = 8.4, 2.1 Hz, 1 H), 7.89 (br d, J = 2.5 Hz, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 4.8 Hz, 1 H), 7.00 (d) , J = 5.0 Hz, 1 H), 4.02 --4.13 (m, 1 H), 3.96 (dd, J = 13.2, 9.2 Hz, 1 H), 3.75 (s, 3 H), 3.33 (br s, 3 H) ), 2.82 --2.91 (m, 1 H), 2.33 (s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 556.1 [M + H] ⁺ . WX161 ( ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 8.18 --8.26 (m, 2 H), 8.17 (s, 1 H), 8.03 (dd, J = 8.4, 1.9 Hz, 1 H), 7.90 (br d, J = 4.5 Hz, 1 H), 7.83 (s, 1 H), 7.72 --7.79 (m, 2 H), 7.55 --7.61 (m, 1 H), 7.48 --7.53 (m, 1 H) , 4.04 --4.11 (m, 1 H), 3.91 --4.00 (m, 1 H), 3.71 (s, 3 H), 2.86 (br dd, J = 14.7, 6.9 Hz, 1 H), 2.48 (br s, 3 H), 2.36 (s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 556.1 [M + H] ⁺ .). The retention times were 4.085 min and 4.702 min, respectively, and the proportion was 1: 1.

Example 87: WX162, WX163

Step 1: Synthesis of compound WX162-2
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (3.0 mL), WX162-1 (103.29 mg, 530.76 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 30 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX162-2 was obtained. MS-ESI m / z: 526.2 [M + H] ⁺ , 528.2 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX162 and WX163
WX162-2 is separated and purified by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; B%: 45% -45%), and paired. WX162 (Rt = 1.972 min) and WX163 (Rt = 0.763 min) were obtained. WX162: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.31 (d, J = 2.0 Hz, 1H), 8.11 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 8.00 (d, J = 2.0 Hz, 1H), 7.85 --7.77 (m, 1H), 7.76 --7.65 (m, 1H), 7.54 (d, J = 7.8 Hz, 1H), 7.47 (br d, J = 8.0 Hz, 1H), 7.40 (dt, J = 5.3, 8.0 Hz, 1H), 7.24 --7.20 (m, 1H), 6.93 (br s, 1H), 5.51 (br d, J = 4.3 Hz, 1H), 4.11 (dd, J = 5.1) , 13.2 Hz, 1H), 4.03 --3.90 (m, 1H), 3.82 (s, 3H), 2.99 --2.75 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H). WX163: ¹ H NMR (400MHz, Methanol-d4) δ: 8.41 (d, J = 2.0 Hz, 1H), 8.30 --8.14 (m, 2H), 8.06 (dt, J = 2.3, 4.3 Hz, 2H), 7.79 (d, J = 8.5 Hz, 1H), 7.64 --7.74 (m, 3H), 7.40 --7.22 (m, 1H), 4.26 (dd, J = 4.8, 13.3 Hz, 1H), 4.04 (dd, J = 9.8) , 13.3 Hz, 1H), 3.81 (s, 3H), 3.08 --2.92 (m, 1H), 2.64 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H).

Example 88: WX164, WX165

Step 1: Synthesis of compound WX164-2
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (3.0 mL), WX164-1 (129.26 mg, 612.41 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 30 ° C for 1 hour to react. finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX164-2 was obtained. MS-ESI m / z: 542.0 [M + H] ⁺ , 544.0 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX164 and WX165
WX164-2 is separated and purified by SFC (chromatography column: OD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; B%: 45% -45%) for the purpose. Compounds WX164 (Rt = 6.203 min) and WX165 (Rt = 5.777 min) were obtained. WX164: ¹ H NMR (400MHz, Methanol-d4) δ: 8.42 (s, 1H), 8.28 (d, J = 2.0 Hz, 1H), 8.21 (s, 1H), 8.15 --7.99 (m, 2H), 7.85 (s, 1H), 7.80 (d, J = 8.5 Hz, 1H), 7.71 (d, J = 8.0 Hz, 1H), 7.63 (d, J = 9.0 Hz, 1H), 7.59 --7.34 (m, 1H) , 4.26 (dd, J = 5.0, 13.3 Hz, 1H), 4.16 --3.93 (m, 1H), 3.80 (s, 3H), 3.10 --2.92 (m, 1H), 2.64 (s, 3H), 1.26 (d) , J = 7.0 Hz, 3H). WX165: ¹ H NMR (400MHz, Methanol-d4) δ: 8.29 (d, J = 2.0 Hz, 1H), 8.15 (d, J = 2.3 Hz, 1H), 8.08 (s, 1H), 8.00 --7.91 (m) , 2H), 7.76 --7.71 (m, 1H), 7.67 (d, J = 8.5 Hz, 1H), 7.60 (d, J = 7.8 Hz, 1H), 7.51 (d, J = 9.0 Hz, 1H), 7.45 --7.30 (m, 1H), 4.14 (dd, J = 4.9, 13.4 Hz, 1H), 4.00 --3.84 (m, 1H), 3.68 (s, 3H), 2.95 --2.80 (m, 1H), 2.52 (s) , 3H).

Example 89: WX166, WX167

Step 1: Synthesis of compound WX166-2
Dissolve WX087-3 (0.15 g, 408.27 μmol) in pyridine (3.0 mL), add WX166-1 (121.57 mg, 530.75 μmol) at 25 ^o C, stir the reaction solution at 30 ° C. for 16 hours, and react. Is finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX166-2 was obtained. MS-ESI m / z: 560.1 [M + H] ⁺ , 562.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX166 and WX167
WX166-2 is separated and purified by SFC (chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; B%: 35% -35%) for the purpose. Compounds WX166 (Rt = 0.913 min) and WX167 (Rt = 2.422 min) were obtained. WX166: ¹ H NMR (400MHz, Methanol-d4) δ: 8.29 (d, J = 1.8 Hz, 1H), 8.17 (d, J = 2.0 Hz, 1H), 8.09 (s, 1H), 8.03 --7.92 (m) , 2H), 7.87 (dd, J = 2.0, 6.8 Hz, 1H), 7.74 --7.60 (m, 2H), 7.29 (t, J = 8.7 Hz, 1H), 4.14 (dd, J = 4.8, 13.3 Hz, 1H), 4.03 --3.81 (m, 1H), 3.69 (s, 3H), 3.00 --2.81 (m, 1H), 2.52 (s, 3H), 1.14 (d, J = 7.0 Hz, 3H). WX167: ¹ H NMR (400MHz, Methanol-d4) δ: 8.30 (d, J = 2.0 Hz, 1H), 8.15 --8.05 (m, 2H), 8.01 --7.91 (m, 2H), 7.88 (dd, J = 2.3, 6.8 Hz, 1H), 7.75-7.74 (m, 2H), 7.28 (t, J = 8.8 Hz, 1H), 4.14 (dd, J = 4.9, 13.4 Hz, 1H), 3.93 (dd, J = 9.8) , 13.6 Hz, 1H), 3.71 (s, 3H), 2.95 --2.79 (m, 1H), 2.52 (s, 3H), 1.14 (d, J = 6.8 Hz, 3H).

Example 90: WX168, WX169

Step 1: Synthesis of compound WX168-2
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (3.0 mL), WX168-1 (108.63 mg, 530.75 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 30 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX168-2 was obtained. MS-ESI m / z: 536.1 [M + H] ⁺ , 536.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX168 and WX169
WX168-2 is separated and purified by SFC (chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 55% -55%) for the purpose. Compounds WX168 (Rt = 0.783 min) and WX169 (Rt = 1.910 min) were obtained. WX168: ¹ H NMR (400MHz, Methanol-d4) δ: 8.26 (d, J = 2.0 Hz, 1H), 8.08 (s, 2H), 8.01 --7.83 (m, 2H), 7.67 (d, J = 8.5 Hz) , 1H), 7.51 (s, 1H), 7.46 --7.37 (m, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.14 (dd, J = 4.9, 13.4 Hz, 1H), 3.93 (dd, J = 9.9, 13.4 Hz, 1H), 3.71 (s, 3H), 2.99 --2.82 (m, 1H), 2.52 (s, 3H), 2.20 (s, 6H), 1.14 (d, J = 7.0 Hz, 3H) ). WX169: ¹ H NMR (400MHz, Methanol-d4) δδ: 8.24 (d, J = 2.0 Hz, 1H), 8.10 --8.02 (m, 2H), 7.98 --7.81 (m, 2H), 7.64 (d, J = 8.5 Hz, 1H), 7.51 (s, 1H), 7.43 (br d, J = 8.0 Hz, 1H), 7.16 (d, J = 8.0 Hz, 1H), 4.14 (dd, J = 4.9, 13.4 Hz, 1H) ), 3.92 (dd, J = 9.8, 13.3 Hz, 1H), 3.79 --3.63 (m, 3H), 3.02 --2.80 (m, 1H), 2.52 (s, 3H), 2.26 --2.10 (m, 6H), 1.14 (d, J = 7.0 Hz, 3H).

Example 91: WX170, WX171

Step 1: Synthesis of compound WX170-2
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (3.0 mL), WX170-1 (125.34 mg, 612.40 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 30 ° C for 1 hour to react. finished. The reaction mixture was spin-dried, water (10 mL) was added thereto, washed three times with methylene chloride (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX170-2 was obtained. MS-ESI m / z: 536.1 [M + H] ⁺ , 536.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX170 and WX171
WX170-2 is separated and purified by SFC (chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 55% -55%) for the purpose. Compounds WX170 (Rt = 0.835 min) and WX171 (Rt = 1.735 min) were obtained. WX170: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.22 (d, J = 1.3 Hz, 1H), 8.04 (s, 1H), 8.01 (d, J = 2.3 Hz, 1H), 7.82 (d, J = 2.3 Hz, 1H), 7.77 (s, 1H), 7.72 --7.61 (m, 2H), 7.19 --7.15 (m, 1H), 7.12 --7.06 (m, 1H), 5.68 (br d, J = 4.8 Hz, 1H), 4.10 (dd, J = 5.0, 13.3 Hz, 1H), 3.97 (dd, J = 9.3, 13.3 Hz, 1H), 3.92 --3.84 (m, 3H), 3.02 --2.83 (m, 1H), 2.67 (d, J = 5.0 Hz, 3H), 2.58 (s, 3H), 2.28 (s, 3H), 1.21 (d, J = 6.8 Hz, 3H). WX170: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.21 (s, 1H), 8.13 --7.95 (m, 2H), 7.88 --7.74 (m, 2H), 7.74 --7.53 (m, 2H), 7.38 --7.24 (m, 1H), 7.20 --7.15 (m, 1H), 7.13 --7.02 (m, 1H), 5.72 (br s, 1H), 4.17 --4.04 (m, 1H), 3.97 (dd, J = 9.4, 13.2 Hz, 1H), 3.90 (s, 3H), 2.94 --2.79 (m, 1H), 2.66 (d, J = 4.8 Hz, 3H), 2.58 (s, 3H), 2.27 (s, 3H), 1.21 (d , J = 7.0 Hz, 3H).

Example 92: WX172, WX173

Step 1: Synthesis of compound WX172-3 WX172-1 (2.50 g, 12.00 mmol), WX172-2 (250 mg, 999.60 μmol) and solvent pyridine (5 mL) were added to a pre-dried reaction bottle for an additional 25. The mixture was stirred at ° C. for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate, followed by preparative thin layer chromatography (petroleum ether:). It was separated and purified by ethyl acetate = 1: 1) to obtain the target compound WX172-3.

Step 2: Synthesis of compound WX172-4 Raw materials WX172-3 (160.00 mg, 493.56 μmol), WX034-1 (208.42 mg, 493.56 μmol) and solvent 1,4-dioxane (3 mL), in a pre-dried reaction bottle, Water (0.5 mL) was added, followed by potassium acetate (96.88 mg, 987.13 μmol), replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride ( 36.11 mg, 49.36 μmol) was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 80 ° C. for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then preparative thin layer chromatography (methylene chloride:). It was separated and purified by methanol = 15: 1), and further separated by preparative HPLC to obtain the target compound WX172-4.

Step 3: Synthesis of compounds WX172 and WX173
WX172-4 was separated by SFC (chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 10 min) and paired with enantiomer WX172 (retention time:: 2.586 min) and WX173 (holding time: 2.68 min) were obtained. WX172: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.33 (d, J = 2.1 Hz, 1H), 8.28 (s, 1H), 8.20 (d, J = 2.3 Hz, 1H), 8.01 (dt, J) = 2.3, 4.2 Hz, 2H), 7.75 (d, J = 8.4 Hz, 1H), 7.65 (dd, J = 2.0, 6.7 Hz, 1H), 7.46 --7.74 (m, 1H), 7.16 (dd, J = 8.6, 10.1 Hz, 1H), 4.24 (dd, J = 4.9, 13.4 Hz, 1H), 4.04 (dd, J = 9.8, 13.4 Hz, 1H), 3.84 (s, 3H), 3.06 --2.95 (m, 1H) ), 2.62 (s, 3H), 2.33 (s, 2H), 2.36 --2.29 (m, 1H), 2.36 --2.29 (m, 1H), 1.24 (d, J = 7.0 Hz, 3H). WX173: ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.15 --8.09 (m, 2H), 8.02 (d, J = 1.8 Hz, 1H), 7.87 --7.82 (m, 1H), 7.79 --7.75 (m, 1H), 7.71 --7.66 (m, 1H), 7.34 (br s, 1H), 7.07 (t, J = 9.2 Hz, 1H), 5.65 (br s, 1H) ), 4.22 --4.14 (m, 1H), 4.05 (dd, J = 9.5, 13.2 Hz, 1H), 3.96 (s, 3H), 3.01 --2.91 (m, 1H), 2.74 (d, J = 4.6 Hz, 3H), 2.35 (s, 3H), 1.29 (d, J = 7.1 Hz, 3H).

Example 93: WX174, WX175

Step 1: Synthesis of compound WX174-2 Raw material WX087-3 (200 mg, 544.36 μmol), raw material WX174-1 (170.36 mg, 816.55 μmol) and solvent pyridine (4 mL) are added to a pre-dried reaction bottle. The mixture was further stirred at 25 ° C. for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, purified by preparative HPLC, and separated. The target compound WX174-2 was obtained.

Step 2: Synthesis of compounds WX174, WX175
WX174-2 is separated and purified by SFC (chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 6.5 min) and paired with enantiomer WX174 ( Retention time: 2.704 min) and WX175 (retention time: 2.714 min) were obtained. WX174: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.39 (d, J = 1.8 Hz, 1H), 8.25 --8.23 (m, 1H), 8.19 (s, 1H), 8.08 (d, J = 2.3 Hz) , 1H), 8.04 (dd, J = 2.2, 8.6 Hz, 1H), 7.78 (d, J = 8.6 Hz, 1H), 7.50 (d, J = 8.3 Hz, 2H), 7.41 --7.36 (m, 1H) , 4.24 (dd, J = 4.9, 13.4 Hz, 1H), 4.09 --3.97 (m, 1H), 3.80 (s, 3H), 3.06 --2.93 (m, 1H), 2.65 --2.60 (m, 3H), 2.31 (d, J = 1.8 Hz, 3H), 2.28 --2.26 (m, 1H), 1.24 (d, J = 7.0 Hz, 3H). WX175: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.37 (d, J = 2.1 Hz, 1H), 8.23 (d, J = 2.3 Hz, 1H), 8.19 (s, 1H), 8.07 (d, J) = 2.3 Hz, 1H), 8.03 (dd, J = 2.2, 8.6 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.49 (d, J = 8.3 Hz, 2H), 7.41 --7.36 (m) , 1H), 4.24 (dd, J = 5.0, 13.4 Hz, 1H), 4.03 (dd, J = 9.9, 13.4 Hz, 1H), 3.79 (s, 3H), 3.06 --2.95 (m, 1H), 2.65- 2.59 (m, 3H), 2.30 (d, J = 1.8 Hz, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 94: WX176, WX177

Step 1: Synthesis of compound WX176-2 Raw material WX087-3 (200 mg, 544.36 μmol) was added to a pre-dried reaction bottle and then dissolved in pyridine (5 mL). After that, WX176-1 (183.80 mg, 816.55 μmol) was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform preparative HPLC (method: chromatography column: Nano-micro Kromasil C18 100 * 30 mm 5 μm; The mobile phase was separated by [water (0.1% TFA) -ACN]; B%: 33% -53%, 10 min) to obtain the target compound WX176-2.

Step 2: Synthesis of compounds WX176 and WX177
WX176-2 is separated and purified by SFC (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 6.5 min) to form a pair. Enantiomers WX176 (Rt = 3.140 min) and WX177 (Rt = 3.480 min) were obtained. WX176: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.31 (d, J = 2.2 Hz, 1H), 8.21 (s, 1H), 8.19 (d, J = 2.3 Hz, 1H), 8.03 --7.91 (m) , 3H), 7.77 (d, J = 8.4 Hz, 1H), 7.45 (s, 1H), 7.30 (d, J = 8.3 Hz, 1H), 4.26 (dd, J = 4.9, 13.4 Hz, 1H), 4.05 (dd, J = 9.9, 13.4 Hz, 1H), 3.90 (s, 3H), 3.08 --2.93 (m, 1H), 2.64 (s, 3H), 2.39 (s, 3H), 1.26 (d, J = 7.0) Hz, 3H). WX177: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.28 (d, J = 2.1 Hz, 1H), 8.20 (s, 1H), 8.16 (d, J = 2.2 Hz, 1H), 7.98 --7.91 (m) , 3H), 7.74 (d, J = 8.6 Hz, 1H), 7.44 (d, J = 0.7 Hz, 1H), 7.29 (dd, J = 0.8, 8.1 Hz, 1H), 4.25 (dd, J = 4.9, 13.4 Hz, 1H), 4.04 (dd, J = 9.8, 13.4 Hz, 1H), 3.90 (s, 3H), 3.08 --2.94 (m, 1H), 2.64 (s, 3H), 2.38 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H).

Example 95: WX178, WX179

Step 1: Synthesis of compound WX178-2 Raw material WX087-3 (150 mg, 408.27 μmol) was added to a pre-dried reaction bottle and then dissolved in pyridine (3 mL). After that, WX178-1 (130.20 mg, 612.41 μmol) was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform preparative HPLC (method: chromatography column: Nano-micro Kromasil C18 100 * 30 mm 5 μm; The target compound WX178-2 was obtained by separation with mobile phase: [water (0.1% TFA) -ACN]; B%: 30% -50%, 10 min).

Step 2: Synthesis of compounds WX178 and WX179
WX178-2 is separated and purified by SFC (purification method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 6.5 min) to form a pair. Enantiomers WX178 (Rt = 2.864 min) and WX179 (Rt = 3.136 min) were obtained. WX178: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.38 (d, J = 2.1 Hz, 1H), 8.28 (d, J = 2.3 Hz, 1H), 8.20 (s, 1H), 8.09 --8.00 (m) , 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.67 --7.50 (m, 2H), 7.35 --7.24 (m, 1H), 4.25 (dd, J = 4.9, 13.4 Hz, 1H), 4.05 ( dd, J = 9.9, 13.3 Hz, 1H), 3.83 (s, 3H), 3.10 --2.95 (m, 1H), 2.64 (s, 3H), 1.25 (d, J = 7.0 Hz, 3H). WX179: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.39 (d, J = 2.1 Hz, 1H), 8.29 (d, J = 2.3 Hz, 1H), 8.21 (s, 1H), 8.09 --8.03 (m) , 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.68 --7.79 (m, 2H), 7.30 (ddt, J = 1.6, 4.6, 8.2 Hz, 1H), 4.26 (dd, J = 4.9, 13.4) Hz, 1H), 4.05 (dd, J = 9.8, 13.4 Hz, 1H), 3.83 (s, 3H), 3.08 --2.94 (m, 1H), 2.64 (s, 3H), 1.25 (d, J = 7.0 Hz) , 3H).

Example 96: WX180, WX181

Step 1: Synthesis of compound WX180-2 WX087-3 (200 mg, 544.36 μmol) was added to a pre-dried reaction bottle and dissolved in pyridine (5 mL), followed by WX180-1 (170.36 mg, 816.55 μmol). , 119.13 μL) was added. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine the organic phases, wash with saturated brine (20 mL), dry with anhydrous sodium sulfate, concentrate under reduced pressure, and perform preparative HPLC (method: chromatography column: Nano-micro Kromasil C18 100 * 30 mm 5 μm; The target compound WX180-2 was obtained by separation with mobile phase: [water (0.1% TFA) -ACN]; B%: 31% -51%, 10 min).

Step 2: Synthesis of compounds WX180 and WX181
WX180-2 is separated and purified by SFC (purification method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45%, 6.5 min) to form a pair. Enantiomers WX180 (Rt = 2.958 min) and WX181 (Rt = 3.261 min) were obtained. WX180: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.32 (d, J = 2.1 Hz, 1H), 8.23 --8.15 (m, 2H), 8.04 --7.98 (m, 2H), 7.95 (dd, J = 5.7, 8.8 Hz, 1H), 7.76 (d, J = 8.4 Hz, 1H), 7.16 (dd, J = 2.4, 9.5 Hz, 1H), 7.06 (dt, J = 2.6, 8.4 Hz, 1H), 4.26 ( dd, J = 5.0, 13.4 Hz, 1H), 4.05 (dd, J = 9.8, 13.4 Hz, 1H), 3.87 (s, 3H), 3.08 --2.96 (m, 1H), 2.73 (s, 3H), 2.64 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H). WX181: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.32 (d, J = 2.1 Hz, 1H), 8.22 --8.17 (m, 2H), 8.04 --7.98 (m, 2H), 7.95 (dd, J = 5.7, 8.8 Hz, 1H), 7.76 (d, J = 8.6 Hz, 1H), 7.16 (dd, J = 2.4, 9.5 Hz, 1H), 7.06 (dt, J = 2.6, 8.4 Hz, 1H), 4.26 ( dd, J = 4.9, 13.4 Hz, 1H), 4.05 (dd, J = 9.8, 13.4 Hz, 1H), 3.87 (s, 3H), 3.07 --2.95 (m, 1H), 2.73 (s, 3H), 2.64 (s, 3H), 1.26 (d, J = 7.0 Hz, 3H).

Example 97: WX182, WX183

Step 1: Synthesis of compound WX182-3 Compound WX182-1 (1 g, 4.93 mmol) and pyridine (6 mL) are added sequentially to a pre-dried reaction bottle, and finally compound WX182-2 (1.21 g, 4.93 mmol). , 659.20 μL) was added. The reaction was then replaced with nitrogen gas, and the reaction was completed after stirring at 25 ° C. for 5 hours. The reaction mixture was distilled under reduced pressure to remove the solvent, and the mixture was separated by flash column chromatography (petroleum ether: ethyl acetate = 10: 1 to 5: 1) to obtain the target compound WX182-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.94 (d, J = 2.3 Hz, 1H), 7.90 (d, J = 2.1 Hz, 1H), 7.68 (ddd, J = 2.3, 7.1, 9.3 Hz, 1H) ), 7.63 --7.57 (m, 1H), 7.33 --7.27 (m, 1H), 6.90 (s, 1H), 3.93 --3.79 (m, 3H).

Step 2: Synthesis of compound WX182-4 Compound WX182-3 (0.15 g, 364.00 μmol), compound bis (pinacolato) diboron (101.68 mg, 400.40 μmol), potassium acetate (71.45 mg, 728.00 μmol) in a pre-dried reaction bottle. ) And 1,4-dioxane (3 mL) were added in sequence, replaced with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (26.63 mg, 36.40 μmol). Was added. After that, it was replaced with nitrogen gas, heated to 110 ° C. and stirred for 3 hours, and then the reaction was completed. After lowering the temperature of the reaction solution, it was distilled under reduced pressure to remove the solvent to obtain the target compound WX182-4, which was used as it was in the next step.

Step 3: Synthesis of Compound WX182-5 Compound WX182-4 (0.2 g, 435.59 μmol), Compound WX034-1 (0.13 g, 401.02 μmol), 1,4-dioxane (2 mL), in a pre-dried reaction bottle. Water (0.2 mL) and potassium acetate (118.07 mg, 1.20 mmol) were added in sequence, followed by replacement with nitrogen gas, and finally [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride ( 29.34 mg, 40.10 μmol) was added. The reaction was completed after further replacement with nitrogen gas, heating to 110 ° C. and stirring for 3 hours. After the reaction solution is cooled, it is distilled under reduced pressure to remove the solvent, and preparative TLC (methylene chloride: methanol = 10: 1) and preparative HPLC (chromatography column chromatography column: water s Xbridge Prep OBD C18 150) * 30 mm 10 μm; Mobile phase: [Water (0.04% NH ₃ H ₂ O) -ACN]; B%: 5% -35%, 10 min) to obtain the target compound WX182-5. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.19 (s, 1H), 8.07 --8.00 (m, 3H), 7.79 ( d, J = 8.3 Hz, 1H), 7.61 --7.57 (m, 2H), 4.29 --4.23 (m, 1H), 4.03 (dd, J = 10.1, 13.2 Hz, 1H), 3.85 (s, 3H), 3.01 (s, 1H), 2.62 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Step 4: Synthesis of compounds WX182 and WX183 Compound WX182-5 (0.07 g, 121.43 μmol) is SFC (separation condition: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MEOH]; B%: 45 A pair of enantiomers WX182 (Rt = 3.151min) and WX183 (Rt = 3.458min) were obtained by separation by% -45%, 8.5min). WX182: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.39 (d, J = 1.8 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.05 --7.98 ( m, 3H), 7.77 (d, J = 8.8 Hz, 1H), 7.61 --7.58 (m, 2H), 4.24 (dd, J = 4.8, 13.2 Hz, 1H), 4.03 (dd, J = 9.9, 13.4 Hz) , 1H), 3.84 (s, 3H), 3.04 --2.94 (m, 1H), 2.64 --2.60 (m, 3H), 1.23 (d, J = 7.0 Hz, 3H). WX183: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.38 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.04 --7.98 ( m, 3H), 7.77 (d, J = 8.3 Hz, 1H), 7.62 --7.55 (m, 2H), 4.24 (dd, J = 5.0, 13.4 Hz, 1H), 4.02 (dd, J = 9.9, 13.4 Hz) , 1H), 3.84 (s, 3H), 3.04 --2.96 (m, 1H), 2.62 (s, 3H), 1.23 (d, J = 7.0 Hz, 3H).

Example 98: WX184, WX185

Step 1: Synthesis of compound WX184-2
Sodium nitrite (3.65 g, 52.97 mmol) and water (3.65 g, 52.97 mmol) in a three-necked flask (250 mL) to which a solution of compound WX184-1 (5 g, 35.31 mmol) and hydrochloric acid (50 mL) was added with stirring at 0-5 ° C. 10 mL) of solution was added slowly. After that, it was replaced with nitrogen gas, and the mixture was further stirred for 1 hour. Copper (1.42 g, 10.59 mmol) was added to a solution of water (10 mL) and sulfur dioxide (5 M, 30 mL) (introducing 5 M of sulfur dioxide acetic acid solution at 15 psi pressure, 20 ° C.). After that, it was replaced with nitrogen gas, and the reaction was completed after further stirring for 2 hours. The reaction mixture was added to ice water (200 mL), stirred for 0.5 hours, filtered to obtain a cake, and the cake was spin-dried under reduced pressure to obtain the target compound WX184-2, which was used as it was in the next step. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.84 (s, 1H), 7.75 (s, 1H), 7.54 (s, 1H), 2.49 (s, 3H), 1.56 (s, 1H).

Step 2: Synthesis of compound WX184-3 Compound WX087-3 (0.15 g, 408.27 μmol) and pyridine (6 mL) are added in order to a pre-dried reaction bottle, and finally compound WX184-2 (183.80 mg, 816.55 μmol). ) Was added. After that, it was replaced with nitrogen gas, and the reaction was completed after stirring at 50 ° C. for 5 hours. The reaction mixture was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain compound WX184-3. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 1.8 Hz, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.08 --8.02 (m, 2H), 7.77 (d, J = 8.8 Hz, 1H), 7.61 (s, 1H), 7.53 (s, 1H), 7.45 (s, 1H), 4.24 (dd, J = 5.0, 13.4 Hz, 1H), 4.02 (dd, J = 10.1, 13.2 Hz, 1H), 3.79 (s, 3H), 2.99 (ddd, J = 4.8, 7.0, 9.6 Hz, 1H), 2.64 --2.58 (m, 3H), 2.36 (s, 3H), 1.23 (d, J = 7.0 Hz, 3H).

Step 3: Synthesis of Compounds WX184, WX185 Compound WX184-3 (0.13 g, 233.80 μmol) is SFC (Conditions: Chromatography Column: AS (250 mm * 30 mm, 5 μm); Mobile Phase: [MeOH]; B%: 45% Separation by -45%, 8 min) gave a pair of enantiomer WX184 (RT = 2.70 min) and compound WX185 (RT = 2.97 min). WX184: ^{1 1} H NMR (400 MHz, METHANOL-d ₄ ) δ = 8.32 (d, J = 2.2 Hz, 1H), 8.21 --8.16 (m, 2H), 8.02 --7.98 (m, 2H), 7.76 --7.67 ( m, 2H), 7.16 --7.07 (m, 2H), 4.24 (dd, J = 4.8, 13.6 Hz, 1H), 4.02 (dd, J = 9.9, 13.4 Hz, 1H), 3.84 (s, 3H), 3.06 --2.96 (m, 1H), 2.64 --2.60 (m, 3H), 2.39 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). WX185: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.41 (d, J = 2.2 Hz, 1H), 8.28 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.05 (d, J = 2.2 Hz, 1H), 8.07 (s, 1H), 7.79 (d, J = 8.8 Hz, 1H), 7.62 (s, 1H), 7.54 (s, 1H), 7.46 (s, 1H), 4.58 ( s, 1H), 4.26 (d, J = 4.8 Hz, 1H), 4.23 (d, J = 4.8 Hz, 1H), 4.03 (d, J = 3.5 Hz, 1H), 4.00 (s, 1H), 4.06 ( s, 1H), 3.80 (s, 3H), 2.99 (br s, 1H), 2.62 (s, 3H), 2.37 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 99: WX186, WX187

Step 1: Synthesis of compound WX186-2
Sodium nitrite (4.14 g, 59.93 mmol) and water (10) were added to a three-necked flask (250 mL) containing a solution of compound WX186-1 (5 g, 39.95 mmol) and hydrochloric acid (50 mL) with stirring at 0-5 ° C. The solution of mL) was slowly added dropwise. After that, it was replaced with nitrogen gas, and the mixture was further stirred for 1 hour. Copper (1.61 g, 11.99 mmol) was added to a solution of water (10 mL) and sulfur dioxide (5 M, 30 mL) (introducing 5 M of sulfur dioxide acetic acid solution at 15 psi pressure, 20 ° C.). After that, it was replaced with nitrogen gas, and the mixture was further stirred for 2 hours. After completion of the reaction, the reaction solution was added to ice water (200 mL), stirred for 0.5 hours, filtered to obtain a cake, and the cake was spin-dried under reduced pressure to obtain the target compound WX186-2. Used for. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.67 (s, 1H), 7.59 --7.53 (m, 1H), 7.31 --7.24 (m, 1H), 2.51 (s, 3H).

Step 2: Synthesis of compound WX186-3 Compound WX087-3 (0.15 g, 408.27 μmol) and pyridine (6 mL) are added in order to a pre-dried reaction bottle, and finally compound WX186-2 (170.36 mg, 816.55 μmol). ) Was added. After that, it was replaced with nitrogen gas, and the reaction was completed after stirring at 50 ° C. for 5 hours. The reaction mixture was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain compound WX186-3. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.30 (d, J = 2.2 Hz, 1H), 8.19 --8.14 (m, 2H), 8.00 --7.91 (m, 3H), 7.75 (d, J = 8.8) Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.39 --7.32 (m, 1H), 4.23 (dd, J = 4.8, 13.6 Hz, 1H), 4.02 (dd, J = 9.9, 13.4 Hz) , 1H), 3.87 (s, 3H), 3.00 (br d, J = 11.8 Hz, 1H), 2.61 (s, 3H), 2.45 (s, 3H), 1.23 (d, J = 7.0 Hz, 3H).

Step 3: Synthesis of Compounds WX186 and WX187 Compound WX186-3 (0.13 g, 240.93 μmol) is separated by SFC (Conditions: Chromatography column: AS (250 mm * 30 mm, 5 μm); Mobile phase: [MeOH]; B%: 45 Separation by% -45%, 6.5 min) gave a pair of enantiomer WX186 (Rt = 2.55 min) and compound WX187 (Rt = 3.00 min). WX186: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 1.8 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.08 --8.04 ( m, 2H), 7.78 (d, J = 8.3 Hz, 1H), 7.46 (s, 1H), 7.35 (br d, J = 7.9 Hz, 1H), 7.18 (s, 1H), 4.27 --4.22 (m, 1H), 4.03 (dd, J = 9.6, 13.2 Hz, 1H), 3.80 (s, 3H), 3.05 --2.96 (m, 1H), 2.62 (s, 3H), 2.38 (s, 3H), 1.24 (d , J = 6.6 Hz, 3H). WX187: 1H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.07 (s, 2H) ), 8.07 --8.04 (m, 2H), 7.78 (d, J = 8.8 Hz, 1H), 7.46 (s, 1H), 7.35 (br d, J = 8.3 Hz, 1H), 7.19 (br d, J = 9.2 Hz, 1H), 4.24 (dd, J = 4.8, 13.2 Hz, 1H), 4.03 (dd, J = 10.1, 13.6 Hz, 1H), 3.81 (s, 3H), 3.01 (br dd, J = 7.2, 9.9 Hz, 1H), 2.62 (s, 3H), 2.38 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 100: WX188, WX189

Step 1: Synthesis of compound WX188-2
Sodium nitrite (1.46 g, 21.19 mmol) and water (4) were added to a three-necked flask (250 mL) containing a solution of compound WX188-1 (2 g, 14.12 mmol) and hydrochloric acid (25 mL) with stirring at 0-5 ° C. The solution of mL) was slowly added dropwise. After that, it was replaced with nitrogen gas, and the mixture was further stirred for 1 hour. Copper (569.71 mg, 4.24 mmol) was added to a solution of water (4 mL) and sulfur dioxide (5 M, 12 mL) (introducing 5 M of sulfur dioxide acetic acid solution at 15 psi pressure, 20 ° C.). After that, it was replaced with nitrogen gas, and the mixture was further stirred for 2 hours. After completion of the reaction, the reaction solution was added to ice water (200 mL), stirred for 0.5 hour, filtered to obtain a cake, dried under reduced pressure after the cake was passed, and the target compound WX188-2 was obtained and used as it was in the next step. did. ¹ H NMR (400MHz, CHLOROFORM-d) δ = 8.06 --8.00 (m, 1H), 7.62 (d, J = 7.0 Hz, 1H), 7.40 (t, J = 7.7 Hz, 1H), 2.53 (s, 3H) ).

Step 2: Synthesis of compound WX188-3 Compound WX087-3 (0.15 g, 408.27 μmol) and pyridine (6 mL) are added in order to a pre-dried reaction bottle, and finally compound WX186-2 (183.80 mg, 816.55 μmol). ) Was added. It was then replaced with nitrogen gas and stirred at 50 ° C. for 5 hours. After completion of the reaction, the reaction solution was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain the target compound WX188-3. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.30 (d, J = 2.2 Hz, 1H), 8.19 --8.14 (m, 2H), 8.00 --7.91 (m, 3H), 7.75 (d, J = 8.8) Hz, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.39 --7.32 (m, 1H), 4.23 (dd, J = 4.8, 13.6 Hz, 1H), 4.28 --4.18 (m, 1H), 4.02 (dd, J = 9.9, 13.4 Hz, 1H), 3.87 (s, 3H), 3.00 (br d, J = 11.8 Hz, 1H), 2.61 (s, 3H), 2.45 (s, 3H), 1.23 (d) , J = 7.0 Hz, 3H).

Step 3: Synthesis of Compounds WX188, WX189 Compound WX188-3 (0.13 g, 240.93 μmol) is SFC (chromatographic column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45% -45. A pair of enantiomers WX188 (Rt = 2.67min) and WX189 (Rt = 3.01min) were obtained by separation by%, 6.5min). WX188: 1H NMR (400MHz, METHANOL-d ₄ ) δ = 8.27 (d, J = 2.2 Hz, 1H), 8.17 (s, 1H), 8.15 (s, 1H), 7.97 --7.93 (m, 3H), 7.73 (d, J = 8.8 Hz, 1H), 7.55 (d, J = 7.4 Hz, 1H), 7.36 (t, J = 7.6 Hz, 1H), 4.25 (d, J = 4.8 Hz, 1H), 4.22 (d) , J = 4.8 Hz, 1H), 4.05 (s, 1H), 4.02 (d, J = 3.5 Hz, 1H), 4.00 (s, 1H), 3.87 (s, 3H), 3.00 (ddd, J = 4.8, 6.9, 9.8 Hz, 1H), 2.62 (s, 3H), 2.45 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). WX189: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.30 (d, J = 2.2 Hz, 1H), 8.18 --8.17 (m, 2H), 7.99 --7.93 (m, 3H), 7.76 (s, 1H) ), 7.74 (s, 1H), 7.56 (d, J = 7.0 Hz, 1H), 7.36 (s, 1H), 7.38 (s, 1H), 7.34 (s, 1H), 4.58 (s, 1H), 4.26 (d, J = 4.8 Hz, 1H), 4.22 (d, J = 4.8 Hz, 1H), 4.03 (d, J = 3.5 Hz, 1H), 4.06 (s, 1H), 3.87 (s, 3H), 3.00 (dt, J = 2.2, 4.8 Hz, 1H), 2.62 (s, 3H), 2.45 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Example 101: WX190, WX191

Step 1: Synthesis of compound WX190-2
Sodium nitrite (3.65 g, 52.97 mmol) and water (3.65 g, 52.97 mmol) in a three-necked flask (250 mL) to which a solution of compound WX190-1 (5 g, 35.31 mmol) and hydrochloric acid (50 mL) was added with stirring at 0-5 ° C. It was slowly added dropwise to a solution (10 mL). After that, it was replaced with nitrogen gas, and the mixture was further stirred for 1 hour. Copper chloride (1.42 g, 10.59 mmol) was added to a solution of water (10 mL) and sulfur dioxide (5 M, 30 mL) (introducing 5 M of sulfur dioxide acetic acid solution at 15 psi pressure, 20 ° C.). After that, it was replaced with nitrogen gas, and the reaction was completed after further stirring for 2 hours. The reaction mixture was added to ice water (200 mL), stirred for 0.5 hours, filtered to obtain a cake, and the cake was dried under reduced pressure to obtain the target compound WX190-2, which was used as it was in the next step. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.92 (d, J = 2.2 Hz, 1H), 7.82 (dd, J = 2.4, 8.6 Hz, 1H), 7.60 (d, J = 8.3 Hz, 1H), 2.51 (s, 3H).

Step 2: Synthesis of compound WX190-3 Compound WX087-3 (0.15 g, 408.27 μmol) and pyridine (6 mL) are added in order to a pre-dried reaction bottle, and finally compound WX190-2 (183.80 mg, 816.55 μmol). ) Was added. After that, it was replaced with nitrogen gas, and the reaction was completed after stirring at 50 ° C. for 5 hours. The reaction mixture was cooled, distilled under reduced pressure to remove the solvent, and purified by preparative TLC (methylene chloride: methanol = 10: 1) to obtain compound WX190-3. ^{1 1} H NMR (400MHz, METHANOL-d ₄ ) δ = 8.40 (d, J = 2.2 Hz, 1H), 8.25 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.10 --8.04 (m, 2H), 7.81 --7.73 (m, 2H), 7.63 --7.58 (m, 1H), 7.63 --7.58 (m, 1H), 7.53 --7.78 (m, 1H), 4.25 (dd, J = 4.8, 13.6 Hz, 1H), 4.03 (dd, J = 9.9, 13.4 Hz, 1H), 3.79 (s, 3H), 3.00 (br dd, J = 9.9, 11.6 Hz, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H).

Step 3: Synthesis of Compounds WX190, WX191 Compound WX190-3 (0.15 g, 269.77 μmol) is SFC (separation condition: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 45. Separation by% -45%, 8 min) gave a pair of enantiomer WX190 (RT = 3.267 min) and compound WX191 (RT = 3.682 min). WX190: ¹ H NMR (400MHz, METHANOL-d ₄ ) δ = 8.32 (d, J = 2.2 Hz, 1H), 8.18 (s, 1H), 8.17 (s, 1H), 8.04 (s, 1H), 7.98 ( d, J = 8.6 Hz, 1H), 7.77 --7.69 (m, 2H), 7.59 (dd, J = 2.0, 8.6 Hz, 1H), 7.48 (d, J = 8.3 Hz, 1H), 4.23 (dd, J = 4.8, 13.6 Hz, 1H), 4.02 (dd, J = 9.9, 13.4 Hz, 1H), 3.77 (s, 3H), 3.00 (ddd, J = 4.8, 7.0, 9.6 Hz, 1H), 2.62 (s, 3H), 2.38 (s, 3H), 1.24 (d, J = 7.0 Hz, 3H). WX191: 1H NMR (400MHz, METHANOL-d ₄ ) δ = 8.39 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.19 (s, 1H), 8.08 --8.03 (m, 2H), 7.80 --7.73 (m, 2H), 7.60 (dd, J = 2.0, 8.6 Hz, 1H), 7.50 (d, J = 8.8 Hz, 1H), 4.25 (dd, J = 4.8, 13.6 Hz, 1H), 4.03 ( dd, J = 9.6, 13.2 Hz, 1H), 3.79 (s, 3H), 3.04 --2.96 (m, 1H), 2.62 (s, 3H), 2.40 (s, 3H), 1.24 (d, J = 7.0 Hz) , 3H).

Example 102: WX192, WX193

Step 1: Synthesis of compound WX192-2
WX087-3 (150 mg, 269.58 μmol) and WX192-1 (90 mg, 423.33 μmol) were dissolved in pyridine (2 mL), and the reaction mixture was stirred at 25 ° C. for 16 hours. After completion of the reaction, the reaction mixture was spin-dried, water (10 mL) was added thereto, the mixture was further extracted 3 times with methylene chloride (5 mL), the organic phase was washed with saturated brine (10 mL), and further. The organic phase was spin-dried after drying over anhydrous sodium sulfate and filtering. The crude product was separated by preparative TLC (DCM: MeOH = 20: 1) to obtain the target compound WX192-2.

Step 2: Synthesis of compounds WX192 and WX193
WX192-2 is separated and purified by SFC (separation method: chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 55% -55%). The target compounds WX192 (Rt = 0.638 min) and WX193 (Rt = 1.550 min) were obtained. WX192: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (d, J = 7.03 Hz, 3 H) 2.53 --2.55 (m, 3 H) 2.87 --2.98 (m, 1 H) 3.77 (s, 3 H) 3.98 --4.07 (m, 1 H) 4.10 --4.19 (m, 1 H) 7.53 (br d, J = 4.52 Hz, 2 H) 7.65 --7.76 (m, 1 H) 7.83 (d, J = 8.53) Hz, 1 H) 7.96 (br d, J = 4.52 Hz, 1 H) 8.00 (d, J = 2.01 Hz, 1 H) 8.16 (br d, J = 8.53 Hz, 1 H) 8.25 (s, 1 H) 8.34 (d, J = 1.51 Hz, 1 H) 8.47 (d, J = 2.01 Hz, 1 H). WX193: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.14 (br d, J = 6.78 Hz, 3 H) 2.54 (br s, 3 H) 2.85 --2.99 (m, 1 H) 3.76 (s, 3 H) 4.01 --4.18 (m, 2 H) 7.52 (br d, J = 4.52 Hz, 2 H) 7.70 (br t, J = 9.03 Hz, 1 H) 7.82 (d, J = 8.53 Hz, 1 H) 7.95 (br d, J = 4.52 Hz, 1 H) 8.00 (d, J = 1.76 Hz, 1 H) 8.15 (dd, J = 8.53, 1.76 Hz, 1 H) 8.25 (s, 1 H) 8.33 (d, J = 1.51 Hz, 1 H) 8.46 (d, J = 1.76 Hz, 1 H).

Example 103: WX194, WX195

Step 1: Synthesis of compound WX194-2
WX087-3 (150 mg, 269.58 μmol) and WX194-1 (110 mg, 418.87 μmol) were dissolved in pyridine (2 mL), and the reaction mixture was stirred at 25 ° C. for 40 hours. After completion of the reaction, the reaction mixture was spin-dried, water (10 mL) was added thereto, the mixture was further extracted 3 times with methylene chloride (5 mL), the organic phase was washed with saturated brine (10 mL), and further. The organic phase was spin-dried after drying over anhydrous sodium sulfate and filtering. The crude product was separated by a preparative TLC plate (PE: EA = 0: 1) to obtain the target compound WX192-2.
Step 2: Synthesis of compounds WX194 and WX195
Separation and purification by SFC (separation method: chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 55% -55%), and enantiomer WX194 ( Rt = 0.450 min) and WX195 (Rt = 0.947 min) were obtained. WX194: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.08 (d, J = 7.03 Hz, 3 H) 2.48 (br s, 3 H) 2.81 --2.92 (m, 1 H) 3.66 (s, 3 H) 3.92 --4.12 (m, 2 H) 7.68 --7.78 (m, 2 H) 7.85 --7.95 (m, 3 H) 8.02 --8.14 (m, 2 H) 8.18 (s, 1 H) 8.25 (d, J) = 2.01 Hz, 1 H) 8.37 (s, 1 H). WX195: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ ppm 1.15 (d, J = 7.03 Hz, 3 H) 2.55 (br s, 3 H) 2.86 --2.99 (m, 1 H) 3.73 (s, 3) H) 3.98 --4.07 (m, 1 H) 4.13 (td, J = 13.49, 6.15 Hz, 1 H) 7.76 --7.86 (m, 2 H) 7.93 --8.04 (m, 3 H) 8.12 --8.20 (m, 2) H) 8.26 (s, 1 H) 8.33 (d, J = 2.01 Hz, 1 H) 8.47 (d, J = 2.01 Hz, 1 H).

Example 104: WX196, WX197

Step 1: Synthesis of compound WX196-2.

Raw material WX196-1 (3 g, 23.78 mmol) and solvent tetrahydrofuran (100 mL) are added to a pre-dried bite flask, followed by nitromethane (4.35 g, 71.34 mmol, 3.85 mL), tetrabutylammonium fluoride (12.69). g, 47.56 mmol, 98% purity) was added, and the mixture was further stirred at 25 ° C. for 12 hours. After completion of the reaction, water (50 mL) was added to the reaction solution, further extracted with methylene chloride (50 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate and then dried under reduced pressure by a pump for column chromatography. The target compound WX196-2 was obtained by separation and purification by chromatography (petroleum ether: ethyl acetate = 1: 0 to 20: 1). ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 4.58 --4.51 (m, 1H), 4.36 (dd, J = 7.9, 12.3 Hz, 1H), 3.72 --3.67 (m, 3H), 2.97 --2.84 (m, 1H), 2.55 (q, J = 8.6 Hz, 1H), 2.10 --1.97 (m, 2H), 1.96 --1.88 (m, 1H), 1.79 --1.66 (m, 2H), 1.44 --1.44 (m, 1H) , 1.44 (qd, J = 8.3, 12.8 Hz, 1H).

Step 2: Synthesis of compound WX196-3.

Raw material WX196-2 (3.5 g, 18.70 mmol) and solvent methanol (35 mL) were added to a pre-dried bite flask, followed by nickel chloride hexahydrate (6.67 g, 28.05 mmol) at 0 ° C. Sodium borohydride (2.12 g, 56.09 mmol) was added slowly, and the mixture was further stirred at 0 ° C. for 2 hours. After completion of the reaction, ammonium chloride was added to the reaction solution to quench it, dried under reduced pressure with a pump, adjusted to a PH of 3 with an acid, extracted with a small amount of methylene chloride, left to separate, and separated. The aqueous phase is adjusted with alkali until the PH becomes 10, extracted with methylene chloride: methanol = 10: 1 (220 mL × 2), the obtained organic phase is dried with anhydrous sodium sulfate, and then rotationally dried under reduced pressure. Then, the target compound WX196-3 was obtained and directly put into the next reaction. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 3.66 (s, 6H), 2.75 --2.63 (m, 5H), 2.44 --2.37 (m, 2H), 2.22 --2.13 (m, 2H), 1.93 --1.78 ( m, 6H), 1.80 --1.78 (m, 1H), 1.72 --1.55 (m, 5H), 1.39 --1.26 (m, 1H), 1.29 --1.20 (m, 6H).

Step 3: Synthesis of compound WX196-5.

Raw material WX196-3 (2.9 g, 18.45 mmol), raw material WX196-4 (3.99 g, 18.45 mmol) and solvent methylene chloride (30 mL) were added to a pre-dried bite flask, followed by 2,4,6- Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (14.09 g, 22.14 mmol, 13.16 mL, 50% purity) was added and the temperature was lowered to 0 ° C. Then, N, N-diisopropylethylamine (7.15 g, 55.34 mmol, 9.64 mL) was slowly added, and the mixture was further stirred at 25 ° C. for 10 hours. After completion of the reaction, water (20 mL) was added to the reaction solution, extracted with methylene chloride (20 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure by a pump, and flash column. The compound was separated and purified by chromatography (petroleum ether: ethyl acetate = 1: 0 to 1: 1) to obtain the target compound WX196-5. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.45 (d, J = 2.4 Hz, 1H), 7.28 (d, J = 2.2 Hz, 1H), 6.57 (d, J = 8.6 Hz, 1H), 6.59- 6.55 (m, 1H), 5.58 (br s, 2H), 3.74 (s, 3H), 3.57 (td, J = 5.1, 13.2 Hz, 1H), 3.31 (ddd, J = 5.2, 9.6, 13.4 Hz, 1H ), 2.58 --2.52 (m, 1H), 2.48 --2.38 (m, 1H), 2.05 --1.90 (m, 4H), 1.76 --1.66 (m, 3H), 1.44 --1.34 (m, 1H).

Step 4: Synthesis of compound WX196-6.

Raw material WX196-5 (956.3 mg, 2.69 mmol) and solvent ethanol (10 mL) were added to a pre-dried bite flask, followed by formamidine acetate (1.68 g, 16.15 mmol), and at 80 ° C. Stirred for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, the organic phase was extracted with methylene chloride (5 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and rotated under reduced pressure. The mixture was dried, separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 1: 1) to obtain the target compound WX196-6. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.42 (d, J = 2.4 Hz, 1H), 8.03 (s, 1H), 7.81 (dd, J = 2.3, 8.7 Hz, 1H), 7.57 (d, J = 8.8 Hz, 1H), 4.13 --3.99 (m, 2H), 4.13 --3.99 (m, 1H), 3.43 (s, 2H), 3.45 --3.41 (m, 1H), 2.72 --2.63 (m, 1H), 2.56 (q, J = 8.5 Hz, 1H), 2.04 --1.95 (m, 2H), 1.92 --1.82 (m, 3H), 1.75 --1.66 (m, 2H), 1.46 --1.37 (m, 1H), 1.24 ( t, J = 7.2 Hz, 1H), 1.28 --1.21 (m, 1H).

Step 5: Synthesis of compound WX196-7.

Raw material WX196-6 (336.5 mg, 921.36 μmol), solvent tetrahydrofuran (3 mL) and water (1.5 mL) were added to a pre-dried reaction bottle, followed by lithium hydroxide monohydrate (77.33 mg, 1.84 mmol). ) Was added, and the mixture was further stirred at 25 ° C. for 2 hours. After completion of the reaction, add water (1 mL) and methylene chloride (2 mL) to the reaction solution, separate the solutions, adjust the aqueous phase with an acid until PH becomes 4, and add methylene chloride (5 mL x 3) to the reaction solution. The organic phase was added and extracted, and the obtained organic phase was dried over anhydrous sodium sulfate, filtered, and rotary-dried under reduced pressure to obtain the target compound WX196-7, which was directly put into the next reaction. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.41 (d, J = 2.2 Hz, 1H), 8.09 (s, 1H), 7.67 (dd, J = 2.1, 8.7 Hz, 1H), 7.34 (d, J = 8.6 Hz, 1H), 4.19 --4.02 (m, 3H), 2.75 --2.63 (m, 1H), 2.60 --2.52 (m, 1H), 2.08 --1.87 (m, 5H), 1.79 --1.68 (m, 3H) , 1.47 --1.40 (m, 1H).

Step 6: Synthesis of compound WX196-8.

Raw material WX196-7 (304 mg, 865.62 μmol, 1 eq), raw material methylamine (2 M, 649.21 μL) and solvent methylene chloride (3 mL) were added to a pre-dried bite flask, followed by 2,4, 6-Tripropyl-1,3,5,2,4,6-trioxatriphosphorinane-2,4,6-trioxide (661.01 mg, 1.04 mmol, 617.77 μL, 50% purity) was added and 0 ° C. N, N-diisopropylethylamine (335.62 mg, 2.60 mmol, 452.32 μL) was added slowly, and the mixture was further stirred at 25 ° C. for 12 hours. After completion of the reaction, water (2 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), the obtained organic phase was dried over anhydrous sodium sulfate, and then rotary-dried under reduced pressure to perform preparative thinning. The compound was separated and purified by layer chromatography (methylene chloride: methanol = 15: 1) to obtain the target compound WX196-8. 1H NMR (400MHz, CHLOROFORM-d) δ = 8.45 (d, J = 2.2 Hz, 1H), 8.04 (s, 1H), 7.86 (dd, J = 2.3, 8.7 Hz, 1H), 7.62 (d, J = 8.8 Hz, 1H), 4.74 --4.73 (m, 1H), 4.20 --4.13 (m, 1H), 4.12 --4.06 (m, 1H), 2.60 (d, J = 4.9 Hz, 4H), 2.36 (q, J) = 9.0 Hz, 1H), 1.92 --1.92 (m, 1H), 1.99 --1.87 (m, 4H), 1.79 --1.68 (m, 3H), 1.48 --1.36 (m, 1H), 1.48 --1.36 (m, 1H) ), 1.48 --1.36 (m, 1H), 0.08 --0.08 (m, 1H).

Step 7: Synthesis of compound WX196-9.

To the pre-dried reaction bottle, add the raw material WX196-8 (196 mg, 538.11 μmol), the raw material BB-3 (262.04 mg, 591.92 μmol), the solvent 1,4-dioxane (2 mL), and water (0.2 mL). , Then potassium acetate (105.62 mg, 1.08 mmol) was added and replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (39.37 mg, 53.81 μmol, 0.1 eq). ) Was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 90 ° C. for 12 hours. After completion of the reaction, water (5 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate and then rotated and dried under reduced pressure to form a preparative thin layer. The compound was separated and purified by chromatography (methylene chloride: methanol = 15: 1) to obtain the target compound WX196-9.

Step 8: Synthesis of compounds WX196 and WX197
WX196-9 is SFC (chromatography column: Chiralpak AD-H 250 * 30mm id 5 μm; mobile phase: A: CO2, B: MeOH (0.1% NH ₃ H ₂ O); gradient: B% = 42%; flow velocity: 70 g / min; Wavelength: 220 nm; Column temperature: 40 degrees; Back pressure: 100 bar) Separate and purify with a pair of enantiomers WX196 (holding time: 2.41 min) and WX197 (holding time: 3.54 min). Obtained. WX196: 1H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.0 Hz, 1H), 8.28 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.02 (d, J = 2.2 Hz, 1H), 8.01 --8.00 (m, 1H), 8.03 --7.99 (m, 1H), 7.77 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.27 --7.21 (m, 1H), 4.87 (s, 44H), 4.21 --4.14 (m, 1H), 4.12 --4.04 (m, 1H), 3.87 ( s, 3H), 2.87 --2.75 (m, 1H), 2.44 (q, J = 8.7 Hz, 1H), 2.32 (s, 3H), 2.05 --1.93 (m, 2H), 1.77 (br dd, J = 6.2) , 13.9 Hz, 2H), 1.53 --1.42 (m, 1H). WX197: 1H NMR (400MHz, METHANOL-d4) δ = 8.34 (s, 1H), 8.28 (s, 1H), 8.23 (s, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.03- 7.98 (m, 2H), 7.77 (br d, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.26 --7.20 (m, 1H), 4.20 --4.04 (m, 3H) ), 3.87 (s, 4H), 2.81 (br dd, J = 7.6, 16.0 Hz, 1H), 2.44 (q, J = 8.7 Hz, 1H), 2.33 (s, 4H), 2.34 --2.31 (m, 1H) ), 2.34 --2.31 (m, 1H), 2.34 --2.31 (m, 1H), 2.02 --1.94 (m, 3H), 1.77 (br dd, J = 5.8, 13.3 Hz, 3H), 1.51 --1.42 (m, 1H).

Example 105: WX198

Step 1: Synthesis of compound WX198
R001 (300.00 mg, 521.73 μmol) was dissolved in ethanol (20 mL), a methylamine alcohol solution (5 mL) was added, and the mixture was heated to 80 ° C. and stirred overnight. After completion of the reaction, the mixture is cooled to room temperature, the organic solvent is spin-dried, separated by preparative thin layer chromatography (eluent: methanol / methylene chloride / triethylamine = 1: 20: 0.2), and further separated by an HPLC preparative column. Then, the target compound WX198 was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.27 (d, J = 2.0 Hz, 1H), 8.13 --7.99 (m, 3H), 7.91 (d, J = 2.3 Hz, 1H), 7.83 --7.76 (m, 1H), 7.75 --7.76 (m, 1H), 7.21 (br s, 1H), 7.07 --6.98 (m, 1H), 5.80 (br s, 1H), 4.07 (t, J = 6.8 Hz, 2H), 3.91 (s, 3H), 2.76 (d, J = 4.8 Hz, 3H), 2.33 --2.08 (m, 2H), 2.16 --1.93 (m, 2H). MS-ESI m / z: 560.1 [M + H] ⁺ , 562.1 [M + H + 2] ⁺ .

Example 106: WX199

Step 1: Synthesis of compound WX199 Compound tetrahydropyrrole (15.09 mg, 212.24 μmol) and triethylamine (35.79 mg, 353.74 μmol) are dissolved in anhydrous methylene chloride (5 mL), and WX003-2 (100.00 mg) is stirred at 0 ° C. , 176.87 μmol) of methylene chloride (1 mL) solution was added dropwise, and the mixture was stirred at 0 ° C. for 1 hour for reaction. After completion of the reaction, the solvent was removed under reduced pressure, separated by preparative thin layer chromatography (eluent: methanol / methylene chloride / triethylamine = 1: 15: 0.15), and further separated by an HPLC preparative column. Compound WX199 was obtained. ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.36 (d, J = 2.0 Hz, 1H), 8.20 --8.11 (m, 3H), 8.00 (d, J = 2.3 Hz, 1H), 7.92 --7.76 (m, 2H), 7.55 (br s, 1H), 7.27 (br s, 1H), 7.19 --7.07 (m, 1H), 4.20 (t, J = 7.2 Hz, 2H), 4.00 (s, 3H), 3.47 (t) , J = 6.9 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 2.44 --2.33 (m, 2H), 2.28 --2.13 (m, 2H), 2.03 --1.93 (m, 2H), 1.93- 1.79 (m, 2H). MS-ESI m / z: 600.1 [M + H] ⁺ , 602.1 [M + H + 2] ⁺ .

Example 107: WX200, WX201

Step 1: Synthesis of compound WX200-1 Compound WX008-4 (150.00 mg, 444.88 μmol), compound BB-3 (236.34 mg, 533.86 μmol), potassium acetate (130.98 mg, 1.33 mmol), ferrocene palladium chloride (32.55 mg,) A mixture of 44.49 μmol), dioxane (3.00 mL) and water (300.00 μL) was stirred in a nitrogen gas atmosphere at 100 ° C. for 2 hours. The reaction mixture was spin-dried, water (30 mL) was added, and then extracted with (methylene chloride / methanol = 10: 1) (30 mL × 3), and the organic phases were combined and saturated saline (30 mL). Wash once with, dry the organic phase with anhydrous sodium sulfate, filter the filtrate and concentrate under reduced pressure by preparative chromatography plate (petroleum ether: ethyl acetate: methylene chloride = 1: 1: 0.5). The mixture was separated and purified to obtain the target compound WX200-1. ^{1 1} H NMR (400MHz, CDCl ₃ ) δ = 8.24 (s, 1H), 8.19 (s, 1H), 8.08 --8.03 (m, 2H), 7.89 (s, 1H), 7.80 --7.67 (m, 2H), 7.22 --7.35 (m, 1H), 7.09 --7.00 (m, 1H), 5.24 --4.99 (m, 1H), 3.90 (s, 3H), 3.42 (s, 3H), 3.26 --3.15 (m, 1H), 3.07 --2.94 (m, 1H), 2.86 --2.77 (m, 3H), 2.68 --2.52 (m, 1H). MS-ESI m / z: 573.1 [M + H] ⁺ .

Step 2: Synthesis of compound WX200-2 Compound WX200-1 (100.00 mg, 174.52 μmol), lithium hydroxide monohydrate (36.61 mg, 872.62 μmol), tetrahydrofuran (1.00 mL), water (1.00 mL) and methanol ( The mixture (1.00 mL) was stirred at 23 ° C. for 1 hour. The reaction was spin-dried, after which water (5 mL) was added, adjusted to pH = 3 with dilute hydrochloric acid (2 N), a pale yellow solid was precipitated, filtered and the cake washed with water (2 mL). Then, the cake was dissolved in methanol (50 mL), and the crude product was obtained by rotary drying to obtain the target compound WX200-2. MS-ESI m / z: 559 [M + H] ⁺ .

Step 3: Synthesis of compound WX200-3 Compound WX200-2 (80.00 mg, 143.12 μmol), methylamine hydrochloride (14.50 mg, 214.68 μmol), 2- (7-benzotriazole) -N, N, N, N- A mixture of tetramethylurea hexafluorophosphate (81.63 mg, 214.68 μmol), triethylamine (43.45 mg, 429.36 μmol, 59.52 μL) and methylene chloride (3.00 mL) was stirred at 20 ° C. for 1 hour, and water (30 mL) was added to the reaction solution. ) Is added, and then extracted with methylene chloride / methanol = 10: 1 (30 mL × 3), the organic phases are combined and washed once with saturated saline (30 mL), and the organic phase is washed with anhydrous sodium sulfate. After drying, the filtrate was filtered and concentrated under reduced pressure, separated and purified by preparative HPLC to give the target compound WX200-3.

Step 4: Synthesis of Compounds WX200 and WX201 Compound WX200-3 is supercritical fluid chromatography (separation condition column: OJ (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O MEOH]; B%: Separation by 35% -35%), and NOE identification gave cis-trans isomers WX200 (cis) and WX201 (trans). WX200 (cis): ¹ H NMR (400MHz, CDCl ₃ ) δ = 8.34 --8.30 (m, 2H), 8.15 --8.09 (m, 2H), 7.97 (d, J = 2.0 Hz, 1H), 7.86 --7.77 ( m, 2H), 7.56 (br s, 1H), 7.25 (d, J = 2.5 Hz, 1H), 7.11 (ddd, J = 2.5, 7.5, 8.8 Hz, 1H), 5.78 (br s, 1H), 5.16 --5.03 (m, 1H), 3.97 (s, 3H), 2.88 (d, J = 5.0 Hz, 3H), 2.86 --2.74 (m, 5H), MS-ESI m / z: 572.1 [M + H] ⁺ .. WX201 (transformer): ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.33 (d, J = 2.0 Hz, 1H), 8.16 --8.07 (m, 3H), 7.98 (d, J = 2.3 Hz, 1H), 7.87 --7.81 (m, 1H), 7.80 --7.74 (m, 1H), 7.53 (br s, 1H), 7.25 (d, J = 2.3 Hz, 1H), 7.16 --7.07 (m, 1H), 5.55 (br d) , J = 4.0 Hz, 1H), 5.22 (quin, J = 8.4 Hz, 1H), 3.98 (s, 3H), 3.16 --3.05 (m, 1H), 3.01 --2.92 (m, 2H), 2.90 (d, J = 5.0 Hz, 3H), 2.89 --2.82 (m, 2H), MS-ESI m / z: 572.1 [M + H] ⁺ . The WX200 and WX201 retention times were 1.529 min and 1.874 min, respectively, and the proportion was 1: 1.

Example 108: WX202

Step 1: Synthesis of compound WX202-2 Compound WX202-1 (10 g, 88.41 mmol) and potassium carbonate (30.55 g, 221.02 mmol) were dissolved in DMF (20.00 mL) and 1,2-dibromoethane (1,2-dibromoethane) was dissolved at 0 ° C. 15.78 g, 83.99 mmol) was added and stirred at 25 ° C. overnight. After completion of the reaction, the mixture was poured into water (100 mL) and extracted 3 times with methylene chloride (100 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure, and purification was performed by column chromatography (ethyl acetate / petroleum ether = 0% -10%) to obtain the target compound WX202-2. ¹ H NMR (400 MHz, CDCl ₃ ) δ: 4.28 (q, J = 7.2 Hz, 2H), 1.76 --1.57 (m, 4H), 1.35 (t, J = 7.2 Hz, 3H).

Step 2: Synthesis of Compound WX202-3 Compound WX202-2 (8 g, 57.49 mmol) is dissolved in methanol (25.00 mL), Runny Nickel (985.06 mg, 11.50 mmol) is added under nitrogen gas protection, and hydrogen is added. Gas (50 psi) was introduced and stirred at 30 ° C. overnight. After completion of the reaction, the solvent was removed under reduced pressure to obtain the target compound WX202-3. ^{1 1} H NMR (400MHz, CDCl ₃ ) δ: 5.76 (br s, 1H), 4.29 --4.00 (m, 2H), 1.57 --0.95 (m, 7H). MS-ESI m / z: 144.1 [M + H] +.

Step 3: Synthesis of Compound WX202-4 Compound 2-amino-5-bromobenzoic acid (3.0 g, 13.89 mmol) was dissolved in N, N'-dimethylformamide (10.00 mL) and diisopropylethylamine (1.79 g, 13.89 mmol). ), HATU (5.28 g, 13.89 mmol) and WX202-3 (2.49 g, 13.89 mmol) were added, and the mixture was stirred at 25 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (100.00 mL) and extracted 3 times with methylene chloride (100.00 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After removing the desiccant by filtration, the solvent is removed under reduced pressure and separated by a chromatography column (eluent: ethyl acetate / petroleum ether = 0% -20%) to obtain the target compound WX202-4. It was. MS-ESI m / z: 525.1.0 [M + H] ⁺ , 327.1 [M + H + 2] ⁺ .

Step 4: Synthesis of compound WX202-5 Compound WX202-4 (1.0 g, 2.93 mmol) is dissolved in ethanol (40.00 mL), formamidine acetate (915.37 mg, 8.79 mmol) is added, and the temperature is 80 ° C. for 2 hours. Stirred. After completion of the reaction, the organic solvent was spin-dried, poured into water (20.00 mL), and extracted 3 times with methylene chloride (20.00 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX202-5. MS-ESI m / z: 353.0 [M + H] ⁺ , 355.0 [M + H + 2] ⁺ .

Step 5: Synthesis of compound WX202-6
WX202-5 (0.8 g, 2.28 mmol l) is dissolved in tetrahydrofuran (10.00 mL) and water (10.00 mL), lithium hydroxide monohydrate (382.36 mg, 9.11 mmol) is added thereto, and the reaction solution is added. Stir at 30 ° C. for 1 hour, and after completion of the reaction, rotate dry the reaction solution, add water (10 mL) to it, extract 3 times with methylene chloride (10 mL), and concentrate concentrated hydrochloric acid (1 mL) in the aqueous phase. ) Was added dropwise, the mixture was extracted 3 times with methylene chloride (10 mL), dried over anhydrous sodium sulfate, and the organic phase was rotationally dried to obtain the target compound WX202-6. MS-ESI m / z: 324.9 [M + H] ⁺ , 326.9 [M + H + 2] ⁺ .

Step 6: Synthesis of Compound WX202-7 Compound WX202-6 (0.5 g, 1.55 mmol) was dissolved in N, N'-dimethylformamide (5.00 mL) to diisopropylethylamine (199.97 mg, 1.55 mmol) and HATU (588.33 mg). , 1.55 mmol) was further added, and methylamine hydrochloride (104.47 mg, 1.55 mmol) was further added, and the mixture was stirred at 30 ° C. for 2 hours. After completion of the reaction, the mixture was poured into water (20 mL) and extracted 3 times with methylene chloride (20 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering and removing the desiccant, the solvent was removed under reduced pressure to obtain the target compound WX202-7. ¹ H NMR (400MHz, Methanol-d4) δ: 8.48 (s, 1H), 8.45 --8.26 (m, 1H), 7.99 --7.83 (m, 1H), 7.71 --7.46 (m, 1H), 3.87 --3.56 ( m, 2H), 2.88 (s, 3H), 1.56 --1.38 (m, 9H). MS-ESI m / z: 525.1.0 [M + H] ⁺ , 327.1 [M + H + 2] ⁺ .

Step 7: Synthesis of compound WX202 Compound WX202-7 (0.15 g, 338.83 μmol), BB-2 (0.15 g, 338.83 μmol), potassium acetate (133.02 mg, 1.36 mmol) was added to dioxane (2.00 mL) and water (0.20 mL). ), Then [1,1'-bis (diphenylphosphino) ferrocene] dichloropalladium (II) (55.34 mg, 67.77 μmol) was added, heated to 95 ° C under nitrogen gas protection, and stirred for 2 hours. did. After completion of the reaction, the mixture was cooled to room temperature, the organic solvent was spin-dried, poured into water (100 mL), and extracted 3 times with methylene chloride (100 mL). The organic phases obtained from the three extractions were combined and dried over anhydrous sodium sulfate. After filtering to remove the desiccant, the solvent is removed under reduced pressure, separated by preparative thin layer chromatography (eluent: methanol / methylene chloride = 1:20), and further separated by HPLC preparative column. The target compound WX202 was obtained. ^{1 1} H NMR (400MHz, Methanol-d4) δ: 8.48 (s, 1H), 8.34 (d, J = 1.8 Hz, 1H), 8.23 (d, J = 1.5 Hz, 1H), 8.12 (dd, J = 5.8) , 8.8 Hz, 1H), 8.07 --7.92 (m, 2H), 7.78 (d, J = 8.5 Hz, 1H), 7.48 (dd, J = 2.3, 8.5 Hz, 1H), 7.34 --7.16 (m, 1H) , 4.36 (s, 2H), 3.89 (s, 3H), 2.69 (s, 3H), 1.33 --1.13 (m, 4H). MS-ESI m / z: 572.0 [M + H] ⁺ , 574.0 [M + H + 2] ⁺ .

Example 109: WX203, WX204

Step 1: Synthesis of compound WX203-2 Compound WX087-3 (0.3 g, 816.55 μmol) was dissolved in pyridine (5 mL), and compound WX203-1 (157.82 mg, 742.32 μmol, 99.88 μL) was added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried and separated by preparative HPLC (TFA) to obtain the target compound WX203-2. MS-ESI m / z: 538.2 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX203 and WX204 Compound WX203-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; Separation by B%: 55% -55%, flow velocity (ml / min): 80 mL / min) gives a pair of enantiomers WX203 (holding time: 1.089 min) and WX204 (holding time: 3.422 min), proportional. It was 1: 1. WX203: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.25 --8.31 (m, 1 H), 8.22 (d, J = 1.8 Hz, 1 H), 8.19 (s, 1 H), 8.05 (dd) , J = 8.5, 2.0 Hz, 1 H), 7.83 --7.92 (m, 2 H), 7.68 --7.78 (m, 3 H), 7.08 (d, J = 8.8 Hz, 2 H), 4.01 --4.17 (m) , 1 H), 3.86 --4.01 (m, 1 H), 3.81 (s, 3 H), 3.73 (s, 3 H), 2.76 --3.01 (m, 1 H), 2.47 --2.49 (m, 3 H) , 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 538.2 [M + H] ⁺ . WX204: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 --8.31 (m, 1 H), 8.23 (s, 1 H), 8.18 --8.22 (m, 1 H), 8.05 (dd, J = 8.5, 2.0 Hz, 1 H), 7.90 (br d, J = 4.8 Hz, 1 H), 7.85 --7.88 (m, 1 H), 7.76 (d, J = 8.5 Hz, 1 H), 7.72 (d, J = 8.0 Hz, 2 H), 7.09 (d, J = 8.8 Hz, 2 H), 4.02 --4.17 (m, 1 H), 3.85 --4.02 (m, 1 H), 3.82 (s, 3 H), 3.74 (s, 3 H), 2.76 --3.00 (m, 1 H), 2.49 --2.50 (m, 3 H), 1.09 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 538.2 [M + H] ⁺ .

Example 110: WX205, WX206

Step 1: Synthesis of compound WX205-2 Compound WX087-3 (0.3 g, 816.55 μmol) was dissolved in pyridine (5 mL), and compound WX205-1 (158.91 mg, 816.55 μmol, 108.10 μL) was added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried and separated by preparative HPLC (TFA) to obtain the target compound WX205-2. MS-ESI m / z: 526.1 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX205 and WX206 Compound WX205-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B %: 55% -55%, Separation by flow velocity (ml / min): 80 mL / min) to obtain a pair of enantiomers WX205 (holding time: 0.845 min) and WX206 (holding time: 2.551 min), proportional to 1 : It was 1. WX205: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.33 (br s, 1 H), 8.24 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 8.06 (dd, dd, J = 8.5, 2.0 Hz, 1 H), 7.89 (br d, J = 2.5 Hz, 2 H), 7.65 --7.77 (m, 3 H), 7.43 (t, J = 9.7 Hz, 1 H), 7.32 ( t, J = 7.4 Hz, 1 H), 4.03 --4.11 (m, 1 H), 3.92 --4.01 (m, 1 H), 3.67 (s, 3 H), 3.31 (br s, 3 H), 2.86 ( br dd, J = 14.6, 6.8 Hz, 1 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 526.1 [M + H] ⁺ . WX206: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.34 (br s, 1 H), 8.24 (d, J = 2.3 Hz, 1 H), 8.18 (s, 1 H), 8.07 (dd, dd, J = 8.5, 2.3 Hz, 1 H), 7.85 --7.93 (m, 2 H), 7.66 --7.77 (m, 3 H), 7.44 (t, J = 9.3 Hz, 1 H), 7.33 (t, J = 7.7 Hz, 1 H), 4.02 --4.11 (m, 1 H), 3.96 (dd, J = 13.3, 9.0 Hz, 1 H), 3.67 (s, 3 H), 2.86 (br dd, J = 14.6, 7.0 Hz, 1 H), 2.48 (br s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 526.1 [M + H] ⁺ .

Example 111: WX207, WX208

Step 1: Synthesis of compound WX207-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), compound WX207-1 (200.47 mg, 816.55 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution is spin-dried. The compound was separated by preparative HPLC (TFA) to give the desired compound WX207-2. MS-ESI m / z: 576.1 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX207 and WX208 Compound WX207-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O IPA]; Separation was performed by B%: 45% -45%, flow velocity (ml / min): 80 mL / min) to obtain enantiomers WX207 (holding time 5.470 min) and WX208 (holding time 6.027 min). WX207: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 --8.33 (m, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 8.18 (s, 1 H), 8.05 (br d, J = 6.8 Hz, 1 H), 7.82 --7.93 (m, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.58 --7.64 (m, 2 H), 7.53 (br d, J = 8.0 Hz, 1 H), 4.02 --4.11 (m, 1 H), 3.96 (dd, J = 13.3, 9.0 Hz, 1 H), 3.67 (s, 3 H), 3.31 (br s, 3 H), 2.86 (br dd, J = 14.6, 7.0 Hz, 1 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 576.1 [M + H] ⁺ . WX208: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.20 --8.35 (m, 1 H), 8.17 (s, 1 H), 8.03 (br d, J = 8.8 Hz, 1 H), 7.90 ( br d, J = 4.5 Hz, 1 H), 7.81 (br s, 1 H), 7.73 (d, J = 8.5 Hz, 1 H), 7.58 (br d, J = 7.8 Hz, 2 H), 7.49 ( br d, J = 8.3 Hz, 1 H), 4.01 --4.12 (m, 1 H), 3.96 (dd, J = 13.3, 9.3 Hz, 1 H), 3.68 (s, 3 H), 3.31 --3.33 (m) , 3 H), 2.81 --2.91 (m, 1 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 576.1 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 112: WX209, WX2110

Step 1: Synthesis of compound WX209-2 Compound WX087-3 (0.3 g, 816.55 μmol) is dissolved in pyridine (5 mL), and compound WX209-1 (0.350 g, 1.78 mmol) is added thereto to prepare a reaction solution. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried. Separation was performed by preparative HPLC (TFA) to obtain the target compound WX209-2. MS-ESI m / z: 528.1 [M + H] ⁺ .

Step 2: Synthesis of Compounds WX209 and WX210 Compound WX209-2 is supercritical fluid chromatography (separation conditions: chromatography column: AD (250 mm * 50 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; Separation by B%: 55% -55%) gave enantiomers WX209 (holding time 0.801 min) and WX210 (holding time 2.556 min). WX209: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.29 (br s, 1 H), 8.22 --8.27 (m, 1 H), 8.17 (s, 1 H), 8.05 (dd, J = 8.4) , 2.1 Hz, 1 H), 7.89 (br d, J = 2.5 Hz, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.68 (d, J = 4.8 Hz, 1 H), 7.00 ( d, J = 5.0 Hz, 1 H), 4.02 --4.13 (m, 1 H), 3.96 (dd, J = 13.2, 9.2 Hz, 1 H), 3.75 (s, 3 H), 3.33 (br s, 3 H), 2.82 --2.91 (m, 1 H), 2.33 (s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 528.1 [M + H] ⁺ . WX210: ¹ H NMR (400 MHz, DMSO-d ₆ ) δ = 8.26 --8.35 (m, 1 H), 8.25 (d, J = 2.0 Hz, 1 H), 8.17 (s, 1 H), 8.05 (dd) , J = 8.5, 2.3 Hz, 1 H), 7.89 (s, 2 H), 7.75 (d, J = 8.3 Hz, 1 H), 7.67 (br d, J = 5.0 Hz, 1 H), 6.99 (d) , J = 5.0 Hz, 1 H), 4.04 --4.11 (m, 1 H), 3.96 (dd, J = 13.3, 9.3 Hz, 1 H), 3.75 (s, 3 H), 3.33 (br s, 3 H) ), 2.82 --2.92 (m, 1 H), 2.33 (s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 528.1 [M + H] ⁺ . The proportion of the two isomers was 1: 1.

Example 113: WX211 and WX212

Step 1: Synthesis of compound WX211-2 Add WX087-3 (200 mg, 544.36 μmol, 1 eq) and WX211-1 (227.87 mg, 816.54 μmol, 142.42 μL) to a pre-dried 40 mL reaction bottle, followed by Pyridine (6 mL) was added to the mixture. The reaction was stirred at 20 ° C. for 12 hours. After completion of the reaction, 10 mL of water and 10 mL of ethyl acetate were added to the reaction system for dilution, the liquid was separated, the organic phase was collected, and the aqueous phase was extracted with ethyl acetate (5 mL × 3). Combine organic phases, wash with saturated brine (20 mL), dry over anhydrous sodium sulfate, concentrate under reduced pressure, separate and purify by preparative thin layer chromatography (DCM: MeOH = 20: 1). , The target compound WX211-2 was obtained.

Step 2: Synthesis of compounds WX211 and WX212
WX211-2 is separated and purified by SFC (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 20% -20%, 6.5 min), and WX211 (separation method: chromatography column: AS (250 mm * 30 mm, 5 μm); Rt = 2.537 min) and WX212 (Rt = 2.740 min) were obtained. WX211: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.33 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.22 --8.14 (m, 2H), 8.02 --7.96 (m, 2H) , 7.96 --7.95 (m, 1H), 7.79 --7.70 (m, 2H), 4.23 (dd, J = 5.0, 13.3 Hz, 1H), 4.02 (dd, J = 9.8, 13.3 Hz, 1H), 3.78 (s) , 3H), 3.06 --2.92 (m, 1H), 2.62 (d, J = 4.6 Hz, 3H), 1.23 (d, J = 7.1 Hz, 3H). WX212: 1H NMR (400MHz, METHANOL-d4) δ = 8.35 (s, 1H), 8.26 (d, J = 2.2 Hz, 1H), 8.21 --8.14 (m, 2H), 8.04 --7.95 (m, 4H), 7.76 (d, J = 8.4 Hz, 2H), 4.23 (dd, J = 4.9, 13.5 Hz, 1H), 4.06 --3.98 (m, 1H), 3.78 (s, 3H), 3.06 --2.94 (m, 1H) , 2.64 --2.57 (m, 3H), 1.23 (d, J = 7.1 Hz, 3H).

Example 114: WX213, WX214

Step 1: Synthesis of compound WX213-2 Compound WX087-3 (0.2 g, 544.36 μmol) was dissolved in pyridine (3 mL), compound WX213-1 (147.04 mg, 653.24 μmol) was added thereto, and the reaction solution was added. The mixture was stirred under the condition of 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was spin-dried and separated by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound WX213-2.

Step 2: Synthesis of Compound WX213 and WX214 Compound WX213-2 is supercritical fluid chromatography (separation condition: chromatography column: Chiralpak AS-H 250 * 30 5μ; mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B% : 35% -35%) separated to give a pair of enantiomers WX213 (holding time: 4.552 min) and WX214 (holding time: 5.313 min), the proportion being 1: 1. WX213: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.32 (br s, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 8.18 (s, 1 H), 8.04 (br d, J = 7.5 Hz, 1 H), 7.85 --7.91 (m, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.57 (br d, J = 6.3 Hz, 1 H), 7.43 (br d, J = 8.0 Hz, 1 H), 4.03 --4.16 (m, 1 H), 3.92 --4.00 (m, 1 H), 3.70 (s, 3 H) , 2.80 --2.93 (m, 1 H), 2.59 (s, 3 H), 2.48 (br s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 556.1 [M + H] ⁺ . WX214: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.32 (br s, 1 H), 8.25 (d, J = 1.8 Hz, 1 H), 8.18 (s, 1 H), 8.04 (br d, J = 7.5 Hz, 1 H), 7.85 --7.91 (m, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.72 (d, J = 2.0 Hz, 1 H), 7.57 (br d, J = 6.3 Hz, 1 H), 7.43 (br d, J = 8.0 Hz, 1 H), 4.03 --4.16 (m, 1 H), 3.92 --4.00 (m, 1 H), 3.70 (s, 3 H) , 2.80 --2.93 (m, 1 H), 2.59 (s, 3 H), 2.48 (br s, 3 H), 1.08 (d, J = 6.8 Hz, 3 H). MS-ESI m / z: 556.1 [M + H] ⁺ .

Example 115: WX215, WX216

Step 1: Synthesis of compound WX215-2 Compound WX087-3 (0.2 g, 544.36 μmol) is dissolved in pyridine (3 mL), compound WX215-1 (136.29 mg, 653.24 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. According to TLC (ethyl acetate: methanol = 10: 1), it was shown that the raw materials had completely reacted, and the reaction solution was spin-dried. The compound was separated by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound WX215-2.

Step 2: Synthesis of Compound WX215 and WX216 Compound WX215-2 is supercritical fluid chromatography (separation condition: chromatography column: Chiralpak AS-H 250 * 30 5μ; mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B% : 35% -35%) separated to give a pair of enantiomers WX215 (holding time: 4.230 min) and WX216 (holding time: 5.606 min), proportional to 1: 1. WX215: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.18 --8.25 (m, 2 H), 8.17 (s, 1 H), 8.02 (dd, J = 8.5, 1.8 Hz, 1 H), 7.89 ( br d, J = 4.8 Hz, 1 H), 7.81 (s, 1 H), 7.74 (d, J = 8.5 Hz, 1 H), 7.61 (d, J = 7.8 Hz, 1 H), 7.31 --7.43 ( m, 2 H), 4.03 --4.15 (m, 1 H), 3.91 --4.00 (m, 1 H), 3.71 (s, 3 H), 2.82 --2.95 (m, 1 H), 2.54 (d, J = 1.8 Hz, 3 H), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 540.1 [M + H] ⁺ . WX216: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.23 --8.31 (m, 1 H), 8.21 (s, 1 H), 8.18 (s, 1 H), 8.04 (dd, J = 8.4, 2.1) Hz, 1 H), 7.86 --7.92 (m, 1 H), 7.84 (d, J = 2.0 Hz, 1 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.59 (d, J = 7.8 Hz) , 1 H), 7.43 (t, J = 9.0 Hz, 1 H), 7.31 --7.38 (m, 1 H), 4.07 (dd, J = 13.3, 5.5 Hz, 1 H), 3.96 (dd, J = 13.2) , 9.2 Hz, 1 H), 3.70 (s, 3 H), 2.86 (br dd, J = 14.8, 6.8 Hz, 1 H), 2.55 (d, J = 1.8 Hz, 3 H), 2.48 (br s, 3 H), 1.05 --1.11 (m, 3 H). MS-ESI m / z: 540.1 [M + H] ⁺ .

Example 116: WX217, WX218

Step 1: Synthesis of compound WX217-2 Compound WX087-3 (0.2 g, 544.36 μmol) was dissolved in pyridine (5 mL), and compound WX217-1 (183.80 mg, 816.55 μmol, 439.49 μL) was added thereto. The reaction solution was stirred under the condition of 25 ° C. for 10 hours. According to TLC (ethyl acetate: methanol = 10: 1), it was shown that the raw materials had completely reacted, and the reaction solution was spin-dried. The compound was separated by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound WX217-2.

Step 2: Synthesis of Compound WX217 and WX218 Compound WX217-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B% : 55% -55%) separated to give a pair of enantiomers WX217 (holding time: 0.890 min) and WX218 (holding time: 2.551 min), the proportion being 1: 1. WX217: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.30 (br s, 1 H), 8.21 --8.26 (m, 1 H), 8.15 --8.21 (m, 1 H), 8.05 (br d, J) = 8.0 Hz, 1 H), 7.82 --7.94 (m, 2 H), 7.73 --7.82 (m, 1 H), 7.69 (d, J = 8.5 Hz, 1 H), 7.49 --7.58 (m, 1 H) , 7.37 (br d, J = 8.8 Hz, 1 H), 4.01 --4.14 (m, 1 H), 3.91 --4.00 (m, 1 H), 3.66 --3.74 (m, 3 H), 2.86 (br d, J = 7.3 Hz, 1 H), 2.58 --2.68 (m, 3 H), 2.47 --2.49 (m, 3 H), 1.08 (br d, J = 7.0 Hz, 3 H). MS-ESI m / z: 556.3 [M + H] ⁺ . WX218: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.20 --8.28 (m, 2 H), 8.18 (s, 1 H), 8.03 (dd, J = 8.5, 2.0 Hz, 1 H), 7.90 ( br d, J = 4.8 Hz, 1 H), 7.78 --7.77 (m, 1 H), 7.66 --7.77 (m, 2 H), 7.51 (s, 1 H), 7.36 (br d, J = 8.5 Hz, 1 H), 4.04 --4.12 (m, 1 H), 3.90 --4.01 (m, 1 H), 3.60 --3.79 (m, 4 H), 2.81 --2.91 (m, 1 H), 2.64 (s, 3 H) ), 2.48 (br s, 3 H), 1.08 (d, J = 7.0 Hz, 3 H). MS-ESI m / z: 556.3 [M + H] ⁺ .

Example 117: WX219, WX220

Step 1: Synthesis of compound WX219-2
WX087-3 (0.1 g, 272.18 μmol) was dissolved in pyridine (2.0 mL), WX219-1 (56.79 mg, 272.18 μmol) was added at 25 ° C, and the reaction solution was stirred at 28 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX219-2 was obtained. MS-ESI m / z: 540.1 [M + H] ⁺ , 542.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX219 and WX220
WX219-2 is separated and purified by SFC (chromatography column: AD (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ O ETOH]; B%: 55% -55%), and paired. WX219 (Rt = 0.864 min) and WX220 (Rt = 3.075 min) were obtained. WX222: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.26 (d, J = 2.0 Hz, 1H), 8.10 --8.00 (m, 2H), 7.93 (d, J = 2.0 Hz, 1H), 7.84 --7.74 ( m, 1H), 7.74 --7.59 (m, 2H), 7.48 --7.30 (m, 1H), 7.26 (s, 1H), 7.07 (t, J = 7.7 Hz, 1H), 5.51 (br d, J = 4.5) Hz, 1H), 4.17 --4.04 (m, 1H), 3.97 (dd, J = 9.3, 13.3 Hz, 1H), 3.90 (s, 3H), 2.95 --2.80 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 2.25 (d, J = 1.8 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H). WX223: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.26 (d, J = 2.0 Hz, 1H), 8.06 --8.00 (m, 2H), 7.93 (d, J = 2.3 Hz, 1H), 7.79 --7.73 ( m, 1H), 7.73 --7.60 (m, 2H), 7.34 (t, J = 7.0 Hz, 1H), 7.26 (s, 1H), 7.07 (t, J = 7.7 Hz, 1H), 5.50 (br d, J = 4.5 Hz, 1H), 4.15 --4.05 (m, 1H), 4.02 --3.94 (m, 1H), 3.90 (s, 3H), 3.91 --3.85 (m, 1H), 2.95 --2.80 (m, 1H) , 2.67 (d, J = 4.8 Hz, 3H), 2.25 (d, J = 1.5 Hz, 3H), 1.21 (d, J = 7.0 Hz, 3H).

Example 118: WX221, WX222

Step 1: Synthesis of compound WX221-2
WX221-1 (2 g, 14.12 mmol) is dissolved in a mixed solvent of concentrated hydrochloric acid (11.0 mL) and glacial acetic acid (3.0 mL), and an aqueous solution (1.8 mL) of sodium nitrite (1.06 g, 15.36 mmol) at 25 ° C. Was added, and the reaction solution was stirred at 0 ° C. for 1 hour. A glacial acetic acid solution of sulfur dioxide (12.00 mL) and cuprous chloride (33.60 mg, 339.40 μmol) were added, and the reaction mixture was stirred at 30 ° C. for 16 hours. The reaction mixture was spin-dried, ice water (500.0 mL) was added thereto, washed three times with methylene chloride (100.0 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX221-2 was obtained. It was used as it was for the next reaction.

Step 2: Synthesis of compound WX221-3
WX087-3 (0.25 g, 680.46 μmol) was dissolved in pyridine (2.0 mL), WX221-2 (153.17 mg, 680.46 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 28 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10.00 mL) was added thereto, washed three times with methylene chloride (10.00 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX221-3 was obtained. MS-ESI m / z: 556.2 [M + H] ⁺ , 558.2 [M + H + 2] ⁺ .

Step 3: Synthesis of compounds WX221 and WX222
WX221-3 is separated and purified by SFC (chromatography column: AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B%: 40% -40%) to form a pair. Enantiomers WX221 (Rt = 3.891 min) and WX222 (Rt = 4.226 min) were obtained. WX221: ¹ H NMR (400 MHz, 400 MHz, DMSO-d ₆ ) δ: 10.28 (br s, 1H), 8.38 (d, J = 2.3 Hz, 1H), 8.25 (d, J = 2.3 Hz, 1H), 8.18 (s, 1H), 8.05 (dd, J = 2.3, 8.5 Hz, 1H), 7.95 --7.83 (m, 2H), 7.75 (d, J = 8.3 Hz, 1H), 7.69 (d, J = 2.3 Hz) , 1H), 7.59 (dd, J = 2.3, 8.3 Hz, 1H), 7.45 (d, J = 8.3 Hz, 1H), 4.15 --4.02 (m, 1H), 4.14 --3.87 (m, 1H), 3.69 ( s, 3H), 3.32 --3.28 (m, 3H), 2.85 (br dd, J = 6.4, 14.9 Hz, 1H), 2.59 (s, 3H), 1.07 (d, J = 7.0 Hz, 3H). WX222: ¹ H NMR (400MHz, DMSO-d ₆ ) δ: 10.33 (br s, 1H), 8.45 (d, J = 2.0 Hz, 1H), 8.33 (d, J = 2.3 Hz, 2H), 8.26 (s) , 1H), 8.13 (dd, J = 2.0, 8.5 Hz, 2H), 8.05 --7.92 (m, 1H), 7.83 (d, J = 8.5 Hz, 1H), 7.77 (d, J = 2.3 Hz, 1H) , 7.67 (dd, J = 2.3, 8.3 Hz, 1H), 7.53 (d, J = 8.3 Hz, 1H), 4.21 --4.07 (m, 2H), 3.76 (s, 3H), 3.58 --3.44 (m, 3H) ), 2.93 (br dd, J = 6.7, 14.7 Hz, 1H), 2.66 (s, 3H), 1.15 (s, 3H).

Example 119: WX223, WX224

Step 1: Synthesis of compound WX223-2
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (2.0 mL), WX223-1 (86.80 mg, 408.27 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 28 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10 mL) was added thereto, washed three times with methylene chloride (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX223-2 was obtained. MS-ESI m / z: 544.1 [M + H] ⁺ , 546.1 [M + H + 2] ⁺ .

Step 2: Synthesis of compounds WX223 and WX224
WX223-2 is separated and purified by SFC (chromatography column: AS (250 mm * 30 mm, 10 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B%: 40% -40%) to form a pair. Enantiomers WX223 (Rt = 3.544 min) and WX224 (Rt = 3.935 min) were obtained. WX223: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.28 (s, 1H), 8.10 (d, J = 2.0 Hz, 1H), 8.05 (s, 1H), 7.97 (d, J = 2.3 Hz, 1H) , 7.86 --7.75 (m, 1H), 7.75 --7.66 (m, 1H), 7.61 --7.65 (m, 1H), 7.27 (br s, 1H), 7.19 --7.06 (m, 2H), 5.61 (br s, 1H), 4.16 --4.06 (m, 1H), 4.03 --3.95 (m, 1H), 3.88 (s, 3H), 3.90 --3.78 (m, 1H), 2.95 --2.80 (m, 1H), 2.67 (d, J = 5.0 Hz, 3H), 1.22 (s, 3H). WX224: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.35 --8.21 (m, 1H), 8.16 --8.06 (m, 1H), 8.04 (s, 1H), 7.98 (d, J = 2.3 Hz, 1H), 7.85 --7.75 (m, 1H), 7.73 (br d, J = 8.3 Hz, 1H), 7.56 --7.74 (m, 1H), 7.19 --7.03 (m, 2H), 5.49 (br s, 1H), 4.16- 4.07 (m, 1H), 4.05 --3.93 (m, 1H), 3.91 --3.85 (m, 3H), 3.65 (q, J = 6.9 Hz, 2H), 2.94 --2.82 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 1.22 (s, 3H).

Example 120: WX225, WX226

Step 1: Synthesis of compound WX225-2
WX225-1 (1.0 g, 7.99 mmol) is dissolved in a mixed solvent of concentrated hydrochloric acid (5.5 mL) and glacial acetic acid (1.5 mL), and an aqueous solution of sodium nitrite (599.73 mg, 8.69 mmol) (1.8 mL) is used at 25 ° C. Was added, and the reaction solution was stirred at 0 ° C. for 1 hour. A glacial acetic acid solution of sulfur dioxide (12 mL) and cuprous chloride (16.80 mg, 169.70 μmol) were added, and the reaction mixture was stirred at 30 ° C. for 16 hours. The reaction mixture was spin-dried, ice water (500 mL) was added thereto, washed three times with methylene chloride (100 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX225-2 was obtained. It was used as it was for the next reaction.

Step 2: Synthesis of compound WX225-3
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (2.0 mL), WX225-2 (85.18 mg, 408.27 μmol) was added at 25 ° C, and the reaction solution was stirred at 28 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10 mL) was added thereto, washed three times with methylene chloride (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX225-3 was obtained. MS-ESI m / z: 540.1 [M + H] ⁺ , 542.1 [M + H + 2] ⁺ .

Step 3: Synthesis of compounds WX225 and WX226
WX225-3 is separated and purified by SFC (chromatography column: Chiralpak AS-H 250 * 30mm 5 μm; mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 35% -35%) to form a pair. Enantiomers WX225 (Rt = 4.494 min) and WX226 (Rt = 4.868 min) were obtained. WX225: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.27 (d, J = 1.8 Hz, 1H), 8.16 --7.99 (m, 2H), 7.88 (d, J = 2.3 Hz, 1H), 7.81 --7.67 ( m, 2H), 7.62 (dd, J = 2.8, 8.3 Hz, 1H), 7.23 --7.20 (m, 1H), 7.12 --6.94 (m, 2H), 5.55 (br d, J = 4.5 Hz, 1H), 4.20 --4.06 (m, 1H), 3.97 (dd, J = 9.3, 13.3 Hz, 1H), 3.90 (s, 3H), 2.95 --2.81 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H) , 2.60 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H). WX226: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.27 (d, J = 1.8 Hz, 1H), 8.11 --8.00 (m, 2H), 7.88 (d, J = 2.3 Hz, 1H), 7.80 --7.66 ( m, 2H), 7.62 (dd, J = 2.6, 8.4 Hz, 1H), 7.24 --7.20 (m, 1H), 7.24 --7.20 (m, 1H), 7.08 (dt, J = 2.6, 8.1 Hz, 1H) , 5.57 (br d, J = 4.3 Hz, 1H), 4.17 --4.04 (m, 1H), 4.03 --3.91 (m, 1H), 3.93 --3.91 (m, 1H), 3.90 (s, 2H), 3.65 ( q, J = 7.0 Hz, 2H), 2.98-2.79 (m, 1H), 2.67 (d, J = 4.8 Hz, 3H), 2.60 (s, 3H), 1.21 (d, J = 7.0 Hz, 3H).

Example 121: WX227, WX228

Step 1: Synthesis of compound WX227-2
WX227-1 (1.00 g, 6.17 mmol) is dissolved in a mixed solvent of concentrated hydrochloric acid (5.5 mL) and glacial acetic acid (1.5 mL), and an aqueous solution of sodium nitrite (463.24 mg, 6.71 mmol) (1.8 mL) is used at 25 ° C. Was added, and the reaction solution was stirred at 0 ° C. for 1 hour. A glacial acetic acid solution of sulfur dioxide (12.00 mL) and cuprous chloride (14.68 mg, 148.31 μmol) were added, and the reaction mixture was stirred at 30 ° C. for 16 hours. The reaction mixture was spin-dried, ice water (500.0 mL) was added thereto, washed three times with methylene chloride (100.0 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX227-2 was obtained. It was used as it was for the next reaction.

Step 2: Synthesis of compound WX227-3
WX087-3 (0.15 g, 408.27 μmol) was dissolved in pyridine (2.0 mL), WX227-2 (105.25 mg, 428.68 μmol) was added dropwise at 25 ° C, and the reaction solution was stirred at 28 ° C for 16 hours to react. finished. The reaction mixture was spin-dried, water (10 mL) was added thereto, washed three times with methylene chloride (10 mL), the organic phases were combined, dried over anhydrous sodium sulfate, and the organic phase was spin-dried. The target compound WX227-3 was obtained. MS-ESI m / z: 576.0 [M + H] ⁺ , 578.0 [M + H + 2] ⁺ , 580.0 [M + H + 4] ⁺ .

Step 3: Synthesis of compounds WX227 and WX228
WX227-3 is separated and purified by SFC (chromatography column: Chiralpak AS-H 250 * 30mm 5 μm; mobile phase: [0.1% NH ₃ H ₂ OEtOH]; B%: 35% -35%) to form a pair. Enantiomers WX227 (Rt = 4.446 min) and WX228 (Rt = 5.228 min) were obtained. WX227: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.27 8.33 (s, 1H), 8.15 (br s, 1H), 8.05 (s, 1H), 7.98 (br s, 1H), 7.86 --7.77 (m, 1H), 7.76 --7.69 (m, 1H), 7.62 (d, J = 1.3 Hz, 2H), 7.46 (br s, 1H), 5.52 (br s, 1H), 4.15 --4.05 (m, 1H), 4.05 --3.92 (m, 1H), 3.85 (s, 3H), 2.94 --2.80 (m, 1H), 2.67 (d, J = 5.0 Hz, 3H), 1.22 (d, J = 6.8 Hz, 3H). WX228: ¹ H NMR (400MHz, CDCl ₃ ) δ: 8.27 8.34 (d, J = 2.0 Hz, 1H), 8.16 (d, J = 2.3 Hz, 1H), 8.05 (s, 1H), 7.99 (d, J) = 2.3 Hz, 1H), 7.86 --7.77 (m, 1H), 7.77 --7.70 (m, 1H), 7.62 (d, J = 1.8 Hz, 2H), 7.54 --7.74 (m, 1H), 5.50 (br d) , J = 4.5 Hz, 1H), 4.16 --4.07 (m, 1H), 3.98 (dd, J = 9.3, 13.3 Hz, 1H), 3.85 (s, 3H), 2.96 --2.82 (m, 1H), 2.67 ( d, J = 4.8 Hz, 3H), 1.22 (d, J = 7.0 Hz, 3H).

Example 122: WX229, WX230

Step 1: Synthesis of compound WX229-2 Compound WX087-3 (0.15 g, 408.27 μmol) is dissolved in pyridine (3 mL), compound WX229-1 (128.66 mg, 489.93 μmol) is added thereto, and the reaction solution is added. The mixture was stirred under the condition of 25 ° C. for 10 hours. According to TLC (ethyl acetate: methanol = 10: 1), the raw materials were completely warped, and the reaction mixture was spin-dried. The compound was separated by preparative thin layer chromatography (ethyl acetate: methanol = 10: 1) to obtain the target compound WX229-2.

Step 2: Synthesis of Compounds WX229 and WX230 Compound WX229-2 is supercritical fluid chromatography (separation condition: chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [0.1% NH ₃ H ₂ OEt OH]; B %: 55% -55%) separated to give a pair of enantiomers WX229 (holding time: 0.450 min) and WX230 (holding time: 0.908 min), with a proportion of 1: 1. WX229: ¹ HNMR (400 MHz, DMSO-d ₆ ) δ = 8.27 (br s, 2 H), 8.18 (s, 1 H), 8.08 --8.15 (m, 1 H), 8.06 (br d, J = 8.3) Hz, 2 H), 7.86 --7.93 (m, 2 H), 7.75 (d, J = 8.5 Hz, 1 H), 7.68 (t, J = 9.6 Hz, 1 H), 4.07 (br dd, J = 13.4) , 5.6 Hz, 1 H), 3.91 --4.01 (m, 1 H), 3.65 (s, 3 H), 2.78 --2.92 (m, 1 H), 2.49 --2.49 (m, 3 H), 1.08 (br d) , J = 7.0 Hz, 3 H). MS-ESI m / z: 594.1 [M + H] ⁺ . WX230: ¹ HNMR (400 MHz, CHLOROFORM-d) δ ppm 8.36 (s, 1 H), 8.28 (d, J = 1.8 Hz, 1 H), 8.19 (s, 1 H), 8.04 --8.15 (m, 3) H), 7.86 --7.96 (m, 2 H), 7.76 (d, J = 7.8 Hz, 1 H), 7.70 (t, J = 9.5 Hz, 1 H), 4.04 --4.12 (m, 1 H), 3.97 (br dd, J = 13.2, 9.2 Hz, 1 H), 3.64 (s, 3 H), 2.82 --2.91 (m, 1 H), 2.48 --2.48 (m, 3 H), 1.08 (d, J = 6.8) Hz, 3 H). MS-ESI m / z: 594.1 [M + H] ⁺ .

Example 123: WX231, WX232

Step 1: Synthesis of compound WX231-3.
Raw material WX231-1 (1.6 g, 6.74 mmol), raw material WX231-2 (4 g, 68.87 mmol) and solvent tetrahydrofuran (16 mL) were added to a pre-dried bite flask, followed by 1,8-diazabicyclo. Undeca-7-ene (4.62 g, 30.32 mmol, 4.57 mL) was added, and the mixture was further stirred at 50 ° C. for 5 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with methylene chloride (10 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure by a pump, and column chromatographed. It was separated and purified by chromatography (petroleum ether: ethyl acetate = 1: 0 to 30: 1) to obtain the target compound WX231-3. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.50 (d, J = 2.2 Hz, 1H), 8.36 (d, J = 2.4 Hz, 1H), 5.31 (s, 1H), 4.50 --4.44 (m, 1H) ), 0.92 --0.85 (m, 6H).

Step 2: Synthesis of compound WX231-4 Raw material WX231-3 (1.3 g, 5.02 mmol) and solvent glacial acetic acid (15 mL) are added to a pre-dried bite flask, followed by iron powder (2.80 g, 50.18 mmol). Was added slowly, and the mixture was further stirred at 25 ° C. for 2 hours. After completion of the reaction, ethanol (30 mL) was added to the reaction solution, filtered, water (10 mL) was added to the filtrate, extracted with methylene chloride (20 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate. After that, it was dried under reduced pressure with a pump, separated and purified by column chromatography (petroleum ether: ethyl acetate = 1: 0 to 15: 1) to obtain the target compound WX231-4. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.65 (d, J = 2.2 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 4.32 --4.23 (m, 1H), 3.84 --3.74 (m) , 1H), 3.78 (br s, 1H), 0.84 --0.80 (m, 2H), 0.78 --0.75 (m, 2H).

Step 3: Synthesis of compound WX231-6 Raw material WX231-4 (940 mg, 4.10 mmol), raw material WX231-5 (1.03 g, 4.51 mmol, 658.55 μL) and solvent pyridine (10 mL) are placed in a pre-dried bite flask. It was added and further stirred at 25 ° C. for 12 hours. After completion of the reaction, water (10 mL) was added to the reaction solution, extracted with methylene chloride (10 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure with a pump, and column chromatography was performed. (Petroleum ether: ethyl acetate = 1: 1 to 5: 1) was separated and purified to obtain the target compound WX231-6. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.06 (dd, J = 5.9, 9.0 Hz, 1H), 7.94 (d, J = 2.2 Hz, 1H), 7.84 (d, J = 2.2 Hz, 1H), 7.65 (d, J = 2.2 Hz, 1H), 7.65 --7.64 (m, 1H), 7.32 (s, 1H), 7.28 (s, 1H), 7.26 (d, J = 2.2 Hz, 1H), 7.11 (ddd) , J = 2.6, 7.5, 8.8 Hz, 1H), 6.99 (d, J = 2.2 Hz, 1H), 4.31 --4.20 (m, 1H), 1.57 (s, 5H), 0.01 --0.01 (m, 1H).

Step 4: Synthesis of compound WX231-7 Raw material WX231-6 (640 mg, 1.52 mmol), raw material WX113-6 (613.21 mg, 1.67 mmol) and solvent 1,4-dioxane (10 mL) in a pre-dried thumb bottle. , Water (1 mL), followed by potassium acetate (297.92 mg, 3.04 mmol), replaced with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (111.06 mg, 151.78 μmol) was added, the mixture was replaced with nitrogen gas, and the mixture was further stirred at 70 ° C. for 10 hours. After completion of the reaction, water (2 mL) was added to the reaction solution, extracted with methylene chloride (5 mL × 3), and the obtained organic phase was dried over anhydrous sodium sulfate, dried under reduced pressure by a pump, and preparatively diluted. It was separated and purified by layer chromatography (methylene chloride: methanol = 20: 1), and further separated by preparative HPLC to obtain the target compound WX231-7.

Step 5: Synthesis of compounds WX231 and WX232
WX231-7 is separated and purified by SFC (separation method: chromatography column: AD (250 mm * 30 mm, 5 μm); mobile phase: [IPA]; B%: 40% -40%, 5.5 min) to form a pair. Enantiomers WX231 (holding time: 2.868 min) and WX232 (holding time: 2.843 min) were obtained. WX231: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.36 (br s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.06 --7.99 (m, 3H), 7.77 (d, J = 8.6 Hz, 1H), 7.79 --7.74 (m, 1H), 7.48 (dd, J = 2.4, 8.6 Hz, 1H), 7.21 (dt, J = 2.4, 8.4 Hz, 1H), 4.58 (br s, 1H), 4.29 --4.17 (m, 2H), 4.03 (dd, J = 9.8, 13.4 Hz, 1H), 3.06 --2.90 (m, 1H), 2.64 --2.60 (m, 2H), 2.64 - 2.60 (m, 1H), 1.24 (d, J = 7.0 Hz, 3H), 0.75 --0.69 (m, 2H), 0.61 --0.54 (m, 2H), WX232: 1H NMR (400MHz, METHANOL-d4) δ = 8.36 (br s, 1H), 8.27 (d, J = 2.0 Hz, 1H), 8.19 (s, 1H), 8.06 --7.99 (m, 3H), 7.77 (d, J = 8.6 Hz, 1H), 7.79- 7.74 (m, 1H), 7.48 (dd, J = 2.4, 8.6 Hz, 1H), 7.21 (dt, J = 2.4, 8.4 Hz, 1H), 4.58 (br s, 1H), 4.29 --4.17 (m, 2H) ), 4.03 (dd, J = 9.8, 13.4 Hz, 1H), 3.06 --2.90 (m, 1H), 2.64 --2.60 (m, 2H), 2.64 --2.60 (m, 1H), 1.24 (d, J = 7.0) Hz, 3H), 0.75 --0.69 (m, 2H), 0.61 --0.54 (m, 2H).

Example 124: WX233, WX234, WX235, WX236

Step 1: Synthesis of compound WX233-2 Compound WX233-1 (5 g, 43.81 mmol) and tetrahydrofuran (50 mL) are added sequentially to a pre-dried bite flask (250 mL), followed by nitromethane (8.02 g, 131.42 mmol). , 7.10 mL) was added, and finally tetrabutylammonium fluoride trihydrate (27.64 g, 87.61 mmol) was added. It was then replaced with nitrogen gas and stirred at 20 ° C. for 10 hours. After completion of the reaction, the reaction solution is distilled under reduced pressure to remove the solvent, and the mixture is separated and purified by flash column chromatography (petroleum ether: mobile phase ethyl acetate = 20: 1) to obtain the pure product compound WX233. I got -2. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 4.59 --4.41 (m, 1H), 4.35 --4.25 (m, 1H), 3.73 --3.67 (m, 3H), 2.76 --2.51 (m, 2H), 1.21 ( dd, J = 5.3, 7.1 Hz, 3H), 1.04 (dd, J = 1.3, 6.8 Hz, 3H).

Step 2: Synthesis of compound WX233-3 Compound WX233-2 (5.1 g, 29.11 mmol), tetrahydrofuran (50 mL) and water (20 mL) are added in this order to a pre-dried bite flask (100 mL), and finally, Lithium hydroxide monohydrate (2.44 g, 58.23 mmol) was added. It was then replaced with nitrogen gas and stirred at 20 ° C. for 2 hours. After completion of the reaction, the reaction solution is extracted with water (30 mL) and ethyl acetate (50 mL), the organic phase is discarded, the aqueous phase is adjusted to pH = 3 with 1N hydrochloric acid, and further extracted with ethyl acetate (50 mL × 3). The organic phases were combined, washed with saturated sodium chloride (20 mL), dried over anhydrous sodium sulfate, and filtered. Finally, the filtrate was dried under reduced pressure to obtain the target compound WX233-3. It was used as it was in the next process. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 4.65 --4.44 (m, 1H), 4.41 --4.30 (m, 1H), 2.82 --2.52 (m, 2H), 1.27 --1.23 (m, 3H), 1.13- 1.06 (m, 3H).

Step 3: Synthesis of Compound WX233-4 Compound WX233-3 (3 g, 18.62 mmol), methylene chloride (5 mL), triethylamine (2.83 g, 27.92 mmol, 3.89 mL) and in a pre-dried bite flask (40 mL). 2- (7-Benzotriazole) -N, N, N, N-tetramethylurea hexafluorophosphate (8.49 g, 22.34 mmol) was added in that order, and finally 4-methoxy-N-methylbenzylamine (3.38 g, 22.34 mmol) was added. It was then replaced with nitrogen gas and stirred at 25 ° C. for 10 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: mobile phase ethyl acetate = 5: 1 to 1: 1) to obtain compound WX233-4. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 7.21 --7.05 (m, 2H), 6.96 --6.82 (m, 2H), 4.71 --4.27 (m, 4H), 3.84 --3.77 (m, 3H), 3.02- 2.92 (m, 3H), 2.88 --2.53 (m, 2H), 1.23 --1.13 (m, 3H), 1.13 --1.00 (m, 3H).

Step 4: Synthesis of compound WX233-5 Platinum dioxide (308.59 mg, 1.36 mmol) was added to a dry hydrogenated bottle (75 mL) pre-substituted with argon, followed by ethanol (40 mL) and compound WX233-4 ( 4 g, 13.59 mmol) was added. It was then replaced with hydrogen gas and stirred at 20 ° C. with 50 psi hydrogen gas for 10 hours. After completion of the reaction, the temperature of the reaction solution was lowered and then filtered, the cake was washed with methanol (100 mL × 2), the filtrates were combined and dried under reduced pressure to obtain compound WX233-5. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 7.22 --7.12 (m, 2H), 6.96 --6.84 (m, 2H), 4.73 --4.44 (m, 2H), 3.80 --3.76 (m, 3H), 3.35 ( s, 1H), 3.03 --2.98 (m, 2H), 2.95 --2.92 (m, 1H), 2.83 --2.82 (m, 3H), 2.80 --2.75 (m, 1H), 2.59 --2.42 (m, 1H), 1.90 --1.75 (m, 1H), 1.14 --1.06 (m, 3H), 0.98 --0.88 (m, 3H).

Step 5: Synthesis of compound WX233-7
Compound WX233-6 (2.21 g, 10.21 mmol), compound WX233-5 (2.7 g, 10.21 mmol), methylene chloride (50 mL) and N, N, diisopropylethylamine (3.96 g) in a pre-dried bite flask (8 mL). , 30.64 mmol, 5.34 mL) were added in sequence, and finally 1-propanephosphonic acid anhydride (cyclic trimmer) 50% ethyl acetate solution (7.80 g, 12.26 mmol, 7.29 mL, 50% purity) was added. It was then replaced with nitrogen gas and stirred at 20 ° C. for 10 hours. After completion of the reaction, the reaction solution was distilled under reduced pressure to remove the solvent to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: mobile phase ethyl acetate = 5: 1 to 1: 1) to obtain compound WX233-7. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.12 --7.84 (m, 1H), 7.69 --7.61 (m, 1H), 7.24 (dt, J = 2.8, 5.7 Hz, 1H), 7.20 --7.03 (m, 1H) 2H), 6.93 --6.79 (m, 2H), 6.56 (dd, J = 1.6, 8.7 Hz, 1H), 4.68 --4.42 (m, 2H), 3.85 --3.71 (m, 3H), 3.64 --3.50 (m, 1H), 3.26 --3.08 (m, 1H), 3.03 --2.95 (m, 3H), 2.81 --2.74 (m, 1H), 1.22 --1.13 (m, 3H), 1.10 --0.93 (m, 3H).

Step 6: Synthesis of compound WX233-8
Compound WX233-7 (2.5 g, 5.41 mmol), formamidine acetate (3.38 g, 32.44 mmol, 6 eq) and ethanol (30 mL) were added in this order to a pre-dried bite flask (100 mL). It was then replaced with nitrogen gas and stirred at 80 ° C. for 10 hours. After completion of the reaction, the reaction solution was dried under reduced pressure to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: mobile phase ethyl acetate = 5: 1 to 1: 3) to obtain compound WX233-8. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.46 --8.41 (m, 1H), 8.07 --8.00 (m, 1H), 7.91 --7.80 (m, 1H), 7.66 --7.57 (m, 1H), 7.22- 7.00 (m, 2H), 6.91 --6.80 (m, 2H), 4.61 --4.40 (m, 2H), 4.23 --3.87 (m, 2H), 3.80 (s, 3H), 3.00 --2.87 (m, 3H), 2.83 --2.77 (m, 1H), 2.47 --2.30 (m, 1H), 1.32 --1.21 (m, 3H), 1.03 --0.89 (m, 3H).

Step 7: Synthesis of compound WX233-9 Compound WX233-8 (1.3 g, 2.75 mmol), methylene chloride (13 mL) and TFA (6.5 mL) are added in this order to a pre-dried bite flask (40 mL), and finally Trifluoromethanesulfonic anhydride (776.46 mg, 2.75 mmol, 454.07 μL) was added. It was then replaced with nitrogen gas and stirred at 20 ° C. for 10 hours. After completion of the reaction, the reaction solution was slowly quenched with saturated sodium bicarbonate (~ 50 mL) at 0 ° C to pH = 9, then extracted with methylene chloride (100 mL × 3), combined with organic phases, and saturated sodium chloride. It was washed with anhydrous sodium sulfate, dried over anhydrous sodium sulfate, filtered, and finally dried under reduced pressure to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: mobile phase ethyl acetate = 5: 1 to 1: 2) to obtain compound WX193-9. ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.45 (d, J = 2.3 Hz, 1H), 8.15 (s, 1H), 7.90 --7.82 (m, 1H), 7.62 (d, J = 8.7 Hz, 1H) ), 6.50 (br s, 1H), 4.34 (dd, J = 8.0, 13.7 Hz, 1H), 3.73 (dd, J = 6.7, 13.7 Hz, 1H), 2.85 (d, J = 4.6 Hz, 3H), 2.37 --2.26 (m, 1H), 2.25 --2.24 (m, 1H), 1.18 (d, J = 7.0 Hz, 3H), 1.01 (d, J = 6.9 Hz, 3H).

Step 8: Synthesis of Compound WX233-10 Compound WX233-9 (0.5 g, 1.42 mmol), compound BB-3 (628.43 mg, 1.42 mmol), potassium acetate (417.94 mg, 4.26 mmol) in a pre-dried thumb bottle (10 mL). ), The solvent 1,4-dioxane (5 mL) and water (0.5 mL) were added in this order. Then, after replacement with nitrogen gas, [1,1'-bis (diphenylphosphino) ferrocene] palladium (II) dichloride (103.87 mg, 141.95 μmol) was added, further replaced with nitrogen gas, and heated to 100 ° C. And stirred for 5 hours. After completion of the reaction, the reaction solution was cooled, filtered, and distilled under reduced pressure of the filtrate to remove the solvent to obtain a crude product. The crude product was separated and purified by flash column chromatography (petroleum ether: mobile phase ethyl acetate = 5: 1 to 0: 1) to obtain compound WX233-10. ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.36 --8.31 (m, 2H), 8.27 --8.22 (m, 1H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.05 --7.99 (m, m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.6, 8.5 Hz, 1H), 7.23 (dt, J = 2.6, 8.4 Hz, 1H), 4.29 (dd, J = 4.5) , 13.5 Hz, 1H), 3.89 --3.80 (m, 4H), 2.78 --2.69 (m, 3H), 2.38 --2.26 (m, 2H), 1.26 --1.22 (m, 3H), 0.93 (d, J = 6.4) Hz, 3H).

Step 9: Synthesis of compounds WX233, WX234, WX235, WX236 Compound WX233-10 (0.8 g, 1.36 mmol) is SFC (equipment: Thar SFC80 preparative SFC; separation column: Chiralpak AD-H 250 * 30 mm id 5u; mobile phase: A for CO2 and B for EtOH; Gradient: B% = 45%; Flow velocity: 80 g / min; Wavelength: 220 nm; Column temperature 40 ° C; System back pressure: 100 bar; Time: 10 min) WX233 (RT = 1.49min), WX234 (RT = 2.00min), WX235 (RT = 2.83min), WX236 (RT = 3.43min) were obtained. WX233: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.23 (d, J = 2.4 Hz, 1H), 8.11 (dd, J = 5.8, 8.9 Hz, 1H), 8.04 --7.99 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.23 (dt, J = 2.5, 8.4 Hz, 1H), 4.10 --3.93 (m, 2H), 3.87 (s, 3H), 2.59 (s, 3H), 2.40 (td, J = 7.3, 14.1 Hz, 1H), 2.33 --2.25 (m) , 1H), 1.19 (d, J = 7.1 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H). WX234: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.34 (d, J = 2.2 Hz, 1H), 8.27 (s, 1H), 8.24 (d, J = 2.4 Hz, 1H), 8.10 (dd, J = 6.0, 8.8 Hz, 1H), 8.04 --7.99 (m, 2H), 7.91 (br s, 1H), 7.78 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 2.6, 8.6 Hz, 1H) ), 7.24 (dt, J = 2.6, 8.4 Hz, 1H), 4.09 --3.93 (m, 2H), 3.87 (s, 3H), 2.59 (d, J = 4.6 Hz, 3H), 2.40 (td, J = 7.2, 14.2 Hz, 1H), 2.30 (quin, J = 7.1 Hz, 1H), 1.19 (d, J = 6.8 Hz, 3H), 0.98 (d, J = 6.8 Hz, 3H). WX235: ^{1 1} H NMR (400MHz, METHANOL-d4) δ = 8.37 --8.30 (m, 2H), 8.24 (d, J = 2.0 Hz, 1H), 8.14 --8.07 (m, 1H), 8.06 --7.97 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 2.2, 8.8 Hz, 1H), 7.23 (t, J = 8.7 Hz, 1H), 4.30 (br dd, J = 4.6, 13.2 Hz, 1H), 3.90 --3.79 (m, 4H), 2.72 (s, 3H), 2.36 --2.27 (m, 2H), 1.25 (br d, J = 6.4 Hz, 3H), 0.93 (br d, J) = 6.4 Hz, 3H). WX236: ¹ H NMR (400MHz, METHANOL-d4) δ = 8.34 (s, 1H), 8.33 (s, 1H), 8.24 (d, J = 2.2 Hz, 1H), 8.10 (dd, J = 5.8, 8.9 Hz) , 1H), 8.06 --7.96 (m, 2H), 7.79 (d, J = 8.4 Hz, 1H), 7.48 (dd, J = 2.6, 8.6 Hz, 1H), 7.23 (ddd, J = 2.4, 7.9, 8.9 Hz, 1H), 4.60 (s, 1H), 4.30 (dd, J = 4.6, 13.2 Hz, 1H), 3.89 --3.81 (m, 4H), 2.75 --2.70 (m, 3H), 2.36 --2.26 (m, 2H), 1.25 (d, J = 6.4 Hz, 3H), 0.96 --0.88 (m, 3H).

Example 125: WX237, WX238

Step 1: Synthesis of WX237-1
To a 40 mL bite flask was added a solution of WX044-1 (300 mg, 917.07 μmol) in MeOH (3 mL) to a solution of NH ₃ (7 M, 2.62 mL) in methanol (7 M, 1.15 mL). After completion of the addition, the reaction solution was stirred at 25 ° C. for 12 hours under the protection of nitrogen gas. After completion of the reaction, the reaction solution was directly concentrated and washed once with methyl tert-butyl ether (5 mL) to obtain the target compound WX237-1 and used as it was in the next reaction. MS, m / z = 314.1 [M + 1] ⁺ .

Step 2: Synthesis of WX237-2
In a 40 mL bite flask, WX237-1 (250 mg, 564.72 μmol) and BB-3 (176.26 mg, 564.72 μmol) dioxane: water = 10: 1 (3 mL) in a solution of LVDS ₃ (94.88 mg, 1.13 mmol, 43.93 uL) and Pd (dppf) Cl ₂ (41.32 mg, 56.47 μmol, 0.1 eq) were added. After completion of the addition, the reaction solution was stirred at 100 ° C. for 5 hours under the protection of nitrogen gas. After completion of the reaction, the reaction mixture was cooled to room temperature, H ₂ O (5 mL) was added to quench the reaction, and the mixture was further extracted with methylene chloride (10 mL × 3). The organic phases were combined, dried over anhydrous sodium sulfate, concentrated, and further separated and purified by preparative thin layer chromatography (DCM: MeOH = 15: 1) to obtain the target compound WX237-2.

Step 3: Synthesis of WX237 and WX238
WX237-2 was separated by prep-SFC (separation column: AS (250 mm * 30 mm, 5 μm); mobile phase: [MeOH]; B%: 40% -40%) to obtain a pair of enantiomers, each prepared-HPLC. Purified by (Separation column: Luna C18 100 * 30 5 μm; Mobile phase: [H ₂ O (0.1% TFA) -ACN]; B%: 25% -55%, 10 min) and WX237 (Rt = 2.55 min) And WX238 (Rt = 2.56 min) were obtained. WX237: ^{1 1} H NMR (400MHz, CHLOROFORM-d) δ = 8.40 --8.82 (m, 3H), 8.10 (dd, J = 6.0, 8.9 Hz, 1H), 8.04 --7.96 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.50 (dd, J = 2.5, 8.5 Hz, 1H), 7.30 --7.17 (m, 1H), 4.69 (dd, J = 3.7, 13.7 Hz, 1H), 4.46 (dd, J = 3.7, 8.6 Hz, 1H), 4.00 (dd, J = 8.7, 13.8 Hz, 1H), 3.90 (s, 3H); MS, m / z = 548.1 [M + 1] ⁺ . WX238: ¹ H NMR (400MHz, METHANOL-d4) Shift = 8.40 --8.20 (m, 3H), 8.10 (dd, J = 5.8, 8.9 Hz, 1H), 8.04 --7.96 (m, 2H), 7.78 (d, J = 8.4 Hz, 1H), 7.47 (dd, J = 2.5, 8.5 Hz, 1H), 7.30 --7.17 (m, 1H), 4.69 (dd, J = 3.7, 13.7 Hz, 1H), 4.46 (dd, J = 3.7, 8.6 Hz, 1H), 4.00 (dd, J = 8.7, 13.8 Hz, 1H), 3.86 (s, 3H); MS, m / z = 548.1 [M + 1] ⁺ .

Example 1: In vitro evaluation
1. In vitro enzyme activity test The lipokinase reaction was performed under the conditions of appropriate substrate and ATP, and then the kinase activity was detected with the ADP-Glo ^TM kit by two steps. First step: The kinase reaction was terminated, residual ATP was completely removed, leaving only ADP. Second step: Kinase detection reagent was added to convert ADP to ATP, accompanied by a luciferin / luciferase reaction. Finally, it was converted to kinase activity by the output value of the fluorescence value. Table 1 shows the test conditions for PI3K enzyme activity.

Experimental materials and equipment:
1. Enzyme: PI3K alpha Millipore # 14-602-K
PI3K beta Promega # V1751
PI3K delta Millipore # 14-604-K
PI3K gamma Millipore # 14-558-K
2. Kit: ADP-Glo ^TM lipokinase and PIP2: 3PS kit (Promega # V1792)
The kit contains 1 mM PIP2: 3PS, 10 × lipid dilution buffer, 1 M magnesium chloride, 10 mM ATP, 10 mM ADP, ADP-Glo reagent, detection buffer and detection substrate.
3. Reaction well plate: OptiPlate-384, transparent white (PerkinElmer # 6007299)
Reagent preparation:
1.10 × Reaction buffer: 500 mM HEPES, pH 7.5, 500 mM NaCl, 9 mM MgCl ₂ ; BSA: 10% stock solution, homemade
2. Final test system conditions: 1 × Reaction system: 50 mM HEPES, 50 mM NaCl, 3 mM MgCl ₂ , 0.01% BSA (freshly prepared on the day of the experiment), 1% DMSO (v / v) +/- Compound
3. Reaction system: 3 μL enzyme and substrate mixture (1: 1) + 2 μL ATP / MgCl2 mixture + 5 μL ADP-Glo reagent + 10 μL detection reagent.

The specific experimental operation is as follows.
1. Dilution of compound: Transfer 50 nL 100 × compound / DMSO to a test well plate with Echo.
--For PI3Kα, the compound was diluted 3-fold from the maximum concentration of 0.111 mM to give a total of 10 different concentrations.
--For PI3Kβ / PI3Kδ / PI3Kγ, the compound was diluted 3-fold from the maximum concentration of 1.11 mM to give a total of 10 different concentrations.
2. Kinase reaction:
(1) Prepare the compound to be tested and add 50 nL 100 compound solution or DMSO to the appropriate well plate;
(2) Prepare 3.33 plate reaction buffer;
(3) Prepare 3.33 liquid PIP2: 3PS and thaw with vortex for at least 1 minute before using PIP2: 3PS;
(4) Prepare 2.5 mM containing 5.25 mM MgCl ₂ ;
(5) Prepare a 3.33 PI3Kα / PI3Kβ / PI3Kδ / PI3Kγ solution;
(6) The lipokinase solution and the PIP2: 3PS solution were mixed at a volume ratio of 1: 1;
(7) 3.33: Lipokinase buffer and PIP2: 3PS solution are mixed in a volume ratio of 1: 1;
(8) Add 3 μL of a mixed solution of buffer and PIP2: 3PS to the first and second rows of the well plate;
(9) Add 3 μL of a mixed solution of enzyme and PIP2: 3PS to the wells of the well plates other than the first and second rows, centrifuge at 10 s (1000 rpm), and incubate at 23 ° C for 20 min;
(10) Add 2 μL 2.5n 1000 rpm ₂ and shake well;
(11) Cover the well plate and shake well for about 30 s, then incubate the well plate at 23 ° C for 2 h;
(12) Add 5 μL of ADP-Glo reagent containing 10 mM MgCl ₂ ;
(13) Centrifuge at 1000 rpm for 10 s, cover the well plate, shake well for about 30 s, and incubate at 23 ° C for 60 min;
(14) Add 10 μL of kinase detection reagent and add
(15) Centrifuge at 1000 rpm for 10 s and then incubate at 23 ° C for 60 min;
(16) The fluorescence value was measured with an Envision device.
2. In vitro cell activity test In order to reflect the cell activity of the compound, the activity level of the test compound for phosphorylation of PI3K downstream protein Akt in the signal transduction pathway was measured in the MCF7 cell line by the method of ELISA.
Cell culture medium: Complete cell culture medium (RPMI 1640 + 10% serum + 1% L-glutamine + 1% dual antibody)
Serum-free medium (serum-free, RPMI 1640 + 1% L-glutamine + 1% dual antibody)
The specific procedure is as follows:
(1) MCF7 cells (ATCC® HTB-22 ^TM ) were inoculated into 96-well plates so that each well contained 100 μL (2.5 10 ⁴ cells / well) cell complete medium, and 37 ° C., 5% CO Inoculated at ₂ for 24 hours.
(2) Complete cell medium was replaced with 100 μL of serum-free medium and cultured overnight by starvation.
(3) A compound (the initial concentration of the compound was 1 mM, diluted 3-fold to a concentration of 10, and then the compound at each concentration was diluted 100-fold with a serum-free medium) was prepared and diluted. 25 μL was added to the cell-containing well plate.
(4) Incubated for 2 h under the conditions of 37 ° C and 5% CO ₂ .
(5) The cells in the well plate were stimulated with 10 μg / mL insulin (Sigma # I9278-5 mL), incubated for 30 min, and then centrifuged at room temperature at 1000 rpm for 5 min.
(6) 250 μL 1 × balanced salt solution (containing Invitrogen, # 14065-056, ₄ ° C, 1 mM / L Na ₃ VO ₄ ) was added to each well, and the cells were washed once.
(7) Add 100 μL of lysis buffer (trishydroxymethylaminomethane hydrochloride, Invitrogen, # 15567-1000 ml) to each well, shake at 4 ° C for 60 min, and then shake at 4 ° C and 4000 rpm for 10 min. Centrifuged.
(8) Subsequent operation procedures were performed according to the specifications of the ELISA kit (TGR BioSciences # EKT002).
The results are shown in Table 2.

CONCLUSIONS: The compounds of the present invention are capable of sufficiently inhibiting PI3K kinase activity and at the same time have high subtype selectivity for PI3K β / γ / δ. In addition, it can sufficiently inhibit the phosphorylation level of Akt downstream of PI3K in the cell.

Example 2: In vivo study
1. In vivo DMPK research Experimental purpose: Female Balb / c mice were used as test animals, and after a single dose, the blood drug concentration of the compound was measured and the pharmacokinetic behavior was evaluated.

Experimental operation: Twelve healthy adult female Balb / c mice were selected, 6 were in the intravenous injection group, and 6 were in the oral administration group. The test compound was mixed with an appropriate amount of intravenous solvent (10% HP-betaCD: 10% solutol = 1: 1, pH = 8), vortexed and sonicated to 1.0 mg / mL clear. The solution was prepared, filtered through a microporous membrane filter and allowed to stand by. The solvent for the oral administration group was 0.5% MC / 0.2% Tw80, and after mixing the test compound with the solvent, vortex and sonicate to prepare a homogeneous suspension of 1.0 mg / mL and allow it to stand by. It was. After intravenous administration of 1 mg / kg or oral administration of 2 mg / kg and 10 mg / kg mice, whole blood is collected for a certain period of time to prepare plasma, and the drug concentration is analyzed by the LC-MS / MS method. The pharmacokinetic parameters were calculated using Phoenix WinNonlin software (Pharsight, USA). The results are shown in Table 3.

CONCLUSIONS: The compounds of the present invention exhibit high exposure, low clearance and good oral bioavailability in mice.
2. In vivo drug efficacy research
(1) Subcutaneous heterologous transplantation of human breast cancer BT-474 cells into nude mice Tumor model cell culture Human breast cancer BT-474 cells (ATCC, Manassus, Virginia, lot number: HTB-20) were monolayer-cultured in viro. As culture conditions, 10% bovine fetal serum and 1% double antibody were added to Hybri-Care medium, and the cells were cultured in an incubator at 37 ° C and 5% CO ₂ . The usual subculture treatment was performed twice a week using trypsin-EDTA. When cell saturation was 80-90% and the quantity met the requirements, cells were collected, counted and inoculated.

Tumor cell inoculation (tumor inoculation)
One day before cell inoculation, estrogen tablets (Innovative Research, Cat # SE-121, 0.36 mg / 60-day release) were subcutaneously implanted and 0.2 ml (10.2 m) BT-474 cells (Matrigel added, volume 1: 1). ) Was subcutaneously inoculated into the right back of each mouse, and when the average tumor volume reached 188 mm ³ , administration was started in groups.

Preparation of test substance Solvent group: Weigh 2.5 g of methylcellulose in a beaker, add 400 ml of ultrapure water, stir overnight, dissolve completely, transfer to a 500 ml volumetric flask, and increase the volume to 500 ml. did. Then 1 ml of Tween 80 was added and mixed well.

Test Compound Group: A certain amount of the test compound was weighed in a brown dispensing bottle and vortexed by adding a corresponding volume of solvent to obtain a uniform suspension or a clear solution.

Tumor Measurement and Experimental Indicators An experimental indicator is to investigate whether tumor growth has been suppressed, delayed, or cured. Tumor diameter is measured with calipers twice a week. The formula for calculating the tumor volume is as follows.

V = 0.5a × b ²
a and b represent the major and minor diameters of the tumor, respectively.

The antitumor effect of a compound is assessed by TGI (%) or relative tumor growth rate T / C (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows.

TGI (%) = [(1- (Average tumor volume at the end of treatment in a treatment group-Average tumor volume at the start of administration in the treatment group)) / (Average tumor volume at the end of treatment in a solvent control group-Solution Average tumor volume at the start of treatment in the control group)] x 100%.

(2) Subcutaneous heterologous transplantation of human ovarian cancer SK-OV-3 cells into BALB / c nude mice Tumor model cell culture Human ovarian cancer SK-OV-3 cells (ECACC-91091004) were monolayer-cultured in viro. As culture conditions, 10% bovine fetal serum, 100 U / ml penicillin and 100 μg / ml streptomycin were added to McCoy's 5a medium (Gibco, 16600-082), and the cells were cultured at 37 ° C. and 5% CO ₂ . The usual subculture treatment was performed twice a week using trypsin-EDTA. When cell saturation was 80-90% and the quantity met the requirements, cells were collected, counted and inoculated.

Tumor cell inoculation
0.2 ml 10 × 10 ⁶ SK-OV-3 cells were subcutaneously inoculated into the right back of each mouse (PBS: Matrigel = 1: 1). When the average tumor volume reached 200 mm ³ , 48 cancer-bearing mice were divided into 8 groups by a stratified random method so that each group contained 6 mice, and administration was started on the day of grouping. did.

Preparation of test substance Solvent group: 2.0 g of methyl cellulose was weighed in a 500 ml glass bottle, and 399.2 mL of H ₂ O and 0.8 ml Tween 80 were added.

Test Compound Group: A certain amount of the test compound was weighed in a brown dispensing bottle and vortexed by adding a corresponding volume of solvent to obtain a uniform suspension or a clear solution.

Tumor Measurement and Experimental Indicators An experimental indicator is to investigate whether tumor growth has been suppressed, delayed, or cured. Tumor diameter is measured with calipers twice a week. The formula for calculating the tumor volume is as follows.

V = 0.5a × b ²
a and b represent the major and minor diameters of the tumor, respectively.

The antitumor effect of a compound is assessed by TGI (%) or relative tumor growth rate T / C (%). TGI (%) reflects the rate of tumor growth inhibition. TGI (%) is calculated as follows.

TGI (%) = [(1- (Average tumor volume at the end of treatment in a treatment group-Average tumor volume at the start of administration in the treatment group)) / (Average tumor volume at the end of treatment in a solvent control group-Solution Average tumor volume at the start of treatment in the control group)] x 100%.

CONCLUSIONS: The compounds of the present invention can clearly inhibit tumor growth in vivo.

Claims (29)

A compound represented by the formula (I), an isomer thereof or a pharmaceutically acceptable salt thereof.

[During the ceremony,
R ₁ is NH ₂ , C _1-6 alkyl, C selected from H, F, Cl, Br, I, OH, NH ₂ or CN, or optionally substituted with 1, 2 or 3 Rs. Selected from _1-6 heteroalkyl or C _3-6 cycloalkyl-O-;
R ₂ is selected from phenyl or 5- to 6-membered heteroaryl optionally substituted with 1, 2 or 3 R;
R ₃ , R ₄ , and R ₅ are independently selected from H, F, Cl, Br, I, OH, or NH ₂ ;
R ₆ is selected from H or optionally substituted with 1, 2 or 3 Rs C _1-6 alkyl, C _1-6 heteroalkyl, C _3-7 cycloalkyl or _3-6 member heterocycloalkyl Selected from;
R ₇ is selected from H, or from C _1-6 alkyl optionally substituted with 1, 2 or 3 R;
Alternatively, R ₆ and R ₇ together form a 3- to 7-membered ring arbitrarily substituted by 1, 2 or 3 R;
L ₁ is selected from single bonds or from -C _1-6 alkyl-arbitrarily substituted by 1, 2 or 3 R;
L ₂ is selected from single bonds or arbitrarily substituted with 1, 2 or 3 R-C _3-7 cycloalkyl-;
Each R is independently selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally substituted with 1, 2 or 3 _{R'C 1-6} alkyl or C _{1 -6} Selected from heteroalkyl;
Each R'is independently selected from F, Cl, Br, I, OH, NH ₂ , CN, Me or Et;
The 3- to 6-membered heterocycloalkyl and the 5- to 6-membered heteroaryl contain 1-4 heteroatoms independently selected from N, O or S;
The heteroatom or heteroatom group in the C _1-6 heteroalkyl is independently N, -O-, -S-, -NH-, -C (= O) NH-, -C (= O)-or- Selected from C (= O) O-; the number of heteroatoms or heteroatoms is 1, 2, 3 or 4. ] The R is C _1-3 alkyl or C _1-3 alkoxy selected from H, F, Cl, Br, I, OH, NH ₂ , CN or optionally substituted with 1, 2 or 3 R'. The compound according to claim 1, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. The R is Me, Et or Me, Et or selected from H, F, Cl, Br, I, OH, NH ₂ , CN or optionally substituted with 1, 2 or 3 R'.

The compound according to claim 2, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. The R is H, F, Cl, Br, I, OH, NH ₂ , CN, Me, CF ₃ , Et,

The compound according to claim 3, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from the above. The R ₁ is selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or optionally substituted with 1, 2 or 3 Rs, C _1-3 alkyl, C _1-3 alkoxy. , C _1-3 The compound according to any one of claims 1 to 4, which is selected from alkylamino or cyclopropyl-O-, an isomer thereof, or a pharmaceutically acceptable salt thereof. Me, Et, said R ₁ was selected from H, F, Cl, Br, I, OH, NH ₂ , CN, or independently substituted by 1, 2 or 3 R, respectively.

The compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. R ₁ is H, F, Cl, Br, I, OH, NH ₂ , CN, Me, Et, CF ₃ ,

The compound according to claim 6, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from. Any one of claims 1 to 4, wherein R ₂ is selected from phenyl, thiazolyl, frills, oxazolyl, isoxazolyl, pyrrolyl or thienyl optionally substituted by 1, 2 or 3 Rs. A compound, an isomer thereof, or a pharmaceutically acceptable salt thereof. The R ₂ was optionally replaced by 1, 2 or 3 Rs.

The compound according to claim 8, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. The R ₂ is

The compound according to claim 1 or 9, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from. The R ₆ is selected from H or optionally substituted with 1, 2 or 3 Rs from C _1-3 alkyl, C _1-3 heteroalkyl, cyclopropyl, cyclobutyl, oxetanyl or tetrahydrofuranyl. The compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof. Me, Et, said R ₆ was selected from H or optionally substituted with 1, 2 or 3 Rs.

The compound according to claim 11, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from. R ₆ is H, Me, Et, CF ₃ ,

The compound according to claim 1 or 12, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from. The compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof, wherein R ₇ is selected from H, Me, or Et. The structural unit

Was arbitrarily replaced by 1, 2 or 3 Rs

The compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. The structural unit

The compound according to claim 15, an isomer thereof, or a pharmaceutically acceptable salt thereof. Wherein L ₁ is selected from a single bond, or one, two or three -CH ₂ optionally substituted by _{R -, - CH 2 -CH 2} -,

The compound according to any one of claims 1 to 4, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. Wherein L ₁ is a single _{bond, -CH 2 -, - CH 2} -CH 2 -,

The compound according to claim 17, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. Claims 1 to 1, wherein the L ₂ is selected from a single bond or optionally substituted with 1, 2 or 3 Rs-cyclopropyl-, -cyclobutyl- or -cyclopentyl-. 4. The compound according to any one of 4, an isomer thereof, or a pharmaceutically acceptable salt thereof. The L ₂ is a single bond,

The compound according to claim 19, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from. The structural unit

It _{is, -CH 2 -, - CH 2} -CH 2 -,

The compound according to claim 18 or 20, an isomer thereof or a pharmaceutically acceptable salt thereof, which is selected from.
[During the ceremony,
n is selected from 1, 2 or 3;
m is independently selected from 1, 2 or 3;
R ₈ is independently selected from H, F, Cl, Br, I, OH, NH ₂ or independently substituted with 1, 2 or 3 Rs of C _1-3 alkyl. Or selected from C _1-3 alkoxy;
R, R ₁ , R ₃ to R ₇ are as defined in claim 1;
If R ₈ is not H, the carbon atom marked with "*" is a chiral carbon atom, either present in the form of a single enantiomer of (R) or (S), or rich in one enantiomer. Exists. ]
The compound according to any one of claims 1 to 7 or 11 to 16, an isomer thereof, or a pharmaceutically acceptable salt thereof. The R _8s are independently H, F, Cl, Br, I, OH, NH ₂ , Me, Et,

The compound according to claim 22, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. The compound is

[During the ceremony,
m, R, R ₁ , and R ₃ to R ₈ are as defined in claim 1. ]
The compound according to claim 22, an isomer thereof, or a pharmaceutically acceptable salt thereof. The compound is







The compound according to any one of claims 1 to 24, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. The compound is










The compound according to any one of claims 1 to 24, an isomer thereof, or a pharmaceutically acceptable salt thereof, which is selected from. A pharmaceutical composition comprising the compound according to any one of claims 1 to 26 as an active ingredient in an effective therapeutic amount, a pharmaceutically acceptable salt thereof or an isomer thereof, and a pharmaceutically acceptable carrier. Use of the compound according to any one of claims 1 to 26, a pharmaceutically acceptable salt thereof or an isomer thereof, or the pharmaceutical composition according to claim 27 in the production of a drug related to a PI3Kα inhibitor. 28. The use of claim 28, wherein the PI3K inhibitor-related drug is a drug for the treatment of solid tumors.